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Developing TRAIL/TRAIL death receptor-based cancer therapies

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Abstract

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that can initiate the apoptosis pathway by binding to its associated death receptors DR4 and DR5. The activation of the TRAIL pathway in inducing tumor-selective apoptosis leads to the development of TRAIL-based cancer therapies, which include recombinant forms of TRAIL, TRAIL receptor agonists, and other therapeutic agents. Importantly, TRAIL, DR4, and DR5 can all be induced by synthetic and natural agents that activate the TRAIL apoptosis pathway in cancer cells. Thus, understanding the regulation of the TRAIL apoptosis pathway can aid in the development of TRAIL-based therapies for the treatment of human cancer.

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References

  1. Johnstone, R. W., Ruefli, A. A., & Lowe, S. W. (2002). Apoptosis: a link between cancer genetics and chemotherapy. Cell, 108(2), 153–164.

    Article  CAS  Google Scholar 

  2. Jin, Z., & El-Deiry, W. S. (2005). Overview of cell death signaling pathways. Cancer Biology & Therapy, 4(2), 139–163.

    Article  CAS  Google Scholar 

  3. Aubrey, B. J., Kelly, G. L., Janic, A., Herold, M. J., & Strasser, A. (2018). How does p53 induce apoptosis and how does this relate to p53-mediated tumour suppression? Cell Death and Differentiation, 25(1), 104–113. https://doi.org/10.1038/cdd.2017.169.

    Article  CAS  PubMed  Google Scholar 

  4. Wu, G. S. (2009). TRAIL as a target in anti-cancer therapy. Cancer Letters, 285(1), 1–5.

    Article  CAS  Google Scholar 

  5. Walczak, H., Miller, R. E., Ariail, K., Gliniak, B., Griffith, T. S., Kubin, M., et al. (1999). Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nature Medicine, 5(2), 157–163.

    Article  CAS  Google Scholar 

  6. Ashkenazi, A., Pai, R. C., Fong, S., Leung, S., Lawrence, D. A., Marsters, S. A., et al. (1999). Safety and antitumor activity of recombinant soluble Apo2 ligand. The Journal of Clinical Investigation, 104(2), 155–162. https://doi.org/10.1172/JCI6926.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Chuntharapai, A., Dodge, K., Grimmer, K., Schroeder, K., Marsters, S. A., Koeppen, H., et al. (2001). Isotype-dependent inhibition of tumor growth in vivo by monoclonal antibodies to death receptor 4. Journal of Immunology, 166(8), 4891–4898.

    Article  CAS  Google Scholar 

  8. Jin, H., Yang, R., Ross, J., Fong, S., Carano, R., Totpal, K., et al. (2008). Cooperation of the agonistic DR5 antibody apomab with chemotherapy to inhibit orthotopic lung tumor growth and improve survival. Clinical Cancer Research, 14(23), 7733–7740.

    Article  CAS  Google Scholar 

  9. Luster, T. A., Carrell, J. A., McCormick, K., Sun, D., & Humphreys, R. (2009). Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib. Molecular Cancer Therapeutics, 8(2), 292–302. https://doi.org/10.1158/1535-7163.MCT-08-0918.

    Article  CAS  PubMed  Google Scholar 

  10. Marini, P., Junginger, D., Stickl, S., Budach, W., Niyazi, M., & Belka, C. (2009). Combined treatment with lexatumumab and irradiation leads to strongly increased long term tumour control under normoxic and hypoxic conditions. Radiation Oncology, 4, 49. https://doi.org/10.1186/1748-717X-4-49.

    Article  CAS  PubMed  Google Scholar 

  11. Almasan, A., & Ashkenazi, A. (2003). Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy. Cytokine & Growth Factor Reviews, 14(3–4), 337–348.

    Article  CAS  Google Scholar 

  12. Wiley, S. R., Schooley, K., Smolak, P. J., Din, W. S., Huang, C. P., Nicholl, J. K., et al. (1995). Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity, 3, 673–682.

    Article  CAS  Google Scholar 

  13. Kemp, T. J., Moore, J. M., & Griffith, T. S. (2004). Human B cells express functional TRAIL/Apo-2 ligand after CpG-containing oligodeoxynucleotide stimulation. Journal of Immunology, 173(2), 892–899.

    Article  CAS  Google Scholar 

  14. Zamai, L., Ahmad, M., Bennett, I. M., Azzoni, L., Alnemri, E. S., & Perussia, B. (1998). Natural killer (NK) cell-mediated cytotoxicity: differential use of TRAIL and Fas ligand by immature and mature primary human NK cells. The Journal of Experimental Medicine, 188(12), 2375–2380.

    Article  CAS  Google Scholar 

  15. Secchiero, P., Rimondi, E., di Iasio, M. G., Agnoletto, C., Melloni, E., Volpi, I., et al. (2013). C-reactive protein downregulates TRAIL expression in human peripheral monocytes via an Egr-1-dependent pathway. Clinical Cancer Research, 19(8), 1949–1959. https://doi.org/10.1158/1078-0432.CCR-12-3027.

    Article  CAS  PubMed  Google Scholar 

  16. Gandini, M., Gras, C., Azeredo, E. L., Pinto, L. M., Smith, N., Despres, P., et al. (2013). Dengue virus activates membrane TRAIL relocalization and IFN-alpha production by human plasmacytoid dendritic cells in vitro and in vivo. PLoS Neglected Tropical Diseases, 7(6), e2257. https://doi.org/10.1371/journal.pntd.0002257.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang, S., & El-Deiry, W. S. (2003). TRAIL and apoptosis induction by TNF-family death receptors. Oncogene, 22(53), 8628–8633. https://doi.org/10.1038/sj.onc.1207232.

    Article  CAS  Google Scholar 

  18. Jin, Z., Li, Y., Pitti, R., Lawrence, D., Pham, V. C., Lill, J. R., et al. (2009). Cullin3-based polyubiquitination and p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling. Cell, 137(4), 721–735. https://doi.org/10.1016/j.cell.2009.03.015.

    Article  CAS  Google Scholar 

  19. Xu, J., Xu, Z., Zhou, J. Y., Zhuang, Z., Wang, E., Boerner, J., et al. (2013). Regulation of the Src-PP2A interaction in tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. The Journal of Biological Chemistry, 288(46), 33263–33271. https://doi.org/10.1074/jbc.M113.508093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Xu, J., Zhou, J. Y., Xu, Z., Kho, D. H., Zhuang, Z., Raz, A., et al. (2014). The role of Cullin3-mediated ubiquitination of the catalytic subunit of PP2A in TRAIL signaling. Cell Cycle, 13(23), 3750–3758. https://doi.org/10.4161/15384101.2014.965068.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Huang, K., Zhang, J., O'Neill, K. L., Gurumurthy, C. B., Quadros, R. M., Tu, Y., et al. (2016). Cleavage by caspase 8 and mitochondrial membrane association activate the BH3-only protein bid during TRAIL-induced apoptosis. The Journal of Biological Chemistry, 291(22), 11843–11851. https://doi.org/10.1074/jbc.M115.711051.

    Article  CAS  PubMed  Google Scholar 

  22. Werneburg, N. W., Bronk, S. F., Guicciardi, M. E., Thomas, L., Dikeakos, J. D., Thomas, G., et al. (2012). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein-induced lysosomal translocation of proapoptotic effectors is mediated by phosphofurin acidic cluster sorting protein-2 (PACS-2). The Journal of Biological Chemistry, 287(29), 24427–24437. https://doi.org/10.1074/jbc.M112.342238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. MacFarlane, M., Robinson, G. L., & Cain, K. (2012). Glucose—a sweet way to die: metabolic switching modulates tumor cell death. Cell Cycle, 11(21), 3919–3925. https://doi.org/10.4161/cc.21804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Taniguchi, H., Horinaka, M., Yoshida, T., Yano, K., Goda, A. E., Yasuda, S., et al. (2012). Targeting the glyoxalase pathway enhances TRAIL efficacy in cancer cells by downregulating the expression of antiapoptotic molecules. Molecular Cancer Therapeutics, 11(10), 2294–2300. https://doi.org/10.1158/1535-7163.MCT-12-0031.

    Article  CAS  PubMed  Google Scholar 

  25. Yao, W., Oh, Y. T., Deng, J., Yue, P., Deng, L., Huang, H., et al. (2016). Expression of death receptor 4 is positively regulated by MEK/ERK/AP-1 signaling and suppressed upon MEK inhibition. The Journal of Biological Chemistry, 291(41), 21694–21702. https://doi.org/10.1074/jbc.M116.738302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yamaguchi, H., & Wang, H. G. (2004). CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. The Journal of Biological Chemistry, 279(44), 45495–45502. https://doi.org/10.1074/jbc.M406933200.

    Article  CAS  PubMed  Google Scholar 

  27. Iurlaro, R., & Munoz-Pinedo, C. (2016). Cell death induced by endoplasmic reticulum stress. The FEBS Journal, 283(14), 2640–2652. https://doi.org/10.1111/febs.13598.

    Article  CAS  PubMed  Google Scholar 

  28. Huang, Y., Wang, Y., Li, X., Chen, Z., Li, X., Wang, H., et al. (2015). Molecular mechanism of ER stress-induced gene expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in macrophages. The FEBS Journal, 282(12), 2361–2378. https://doi.org/10.1111/febs.13284.

    Article  CAS  PubMed  Google Scholar 

  29. Xu, L., Su, L., & Liu, X. (2012). PKCdelta regulates death receptor 5 expression induced by PS-341 through ATF4-ATF3/CHOP axis in human lung cancer cells. Molecular Cancer Therapeutics, 11(10), 2174–2182. https://doi.org/10.1158/1535-7163.MCT-12-0602.

    Article  CAS  PubMed  Google Scholar 

  30. Lee, D. H., Sung, K. S., Guo, Z. S., Kwon, W. T., Bartlett, D. L., Oh, S. C., et al. (2016). TRAIL-induced caspase activation is a prerequisite for activation of the endoplasmic reticulum stress-induced signal transduction pathways. Journal of Cellular Biochemistry, 117(5), 1078–1091. https://doi.org/10.1002/jcb.25289.

    Article  CAS  PubMed  Google Scholar 

  31. Gupta, S. C., Francis, S. K., Nair, M. S., Mo, Y. Y., & Aggarwal, B. B. (2013). Azadirone, a limonoid tetranortriterpene, induces death receptors and sensitizes human cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) through a p53 protein-independent mechanism: evidence for the role of the ROS-ERK-CHOP-death receptor pathway. The Journal of Biological Chemistry, 288(45), 32343–32356. https://doi.org/10.1074/jbc.M113.455188.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Quast, S. A., Berger, A., & Eberle, J. (2013). ROS-dependent phosphorylation of Bax by wortmannin sensitizes melanoma cells for TRAIL-induced apoptosis. Cell Death & Disease, 4, e839. https://doi.org/10.1038/cddis.2013.344.

    Article  CAS  Google Scholar 

  33. Grunert, M., Gottschalk, K., Kapahnke, J., Gundisch, S., Kieser, A., & Jeremias, I. (2012). The adaptor protein FADD and the initiator caspase-8 mediate activation of NF-kappaB by TRAIL. Cell Death & Disease, 3, e414. https://doi.org/10.1038/cddis.2012.154.

    Article  CAS  Google Scholar 

  34. Keuper, M., Wernstedt Asterholm, I., Scherer, P. E., Westhoff, M. A., Moller, P., Debatin, K. M., et al. (2013). TRAIL (TNF-related apoptosis-inducing ligand) regulates adipocyte metabolism by caspase-mediated cleavage of PPARgamma. Cell Death & Disease, 4, e474. https://doi.org/10.1038/cddis.2012.212.

    Article  CAS  Google Scholar 

  35. Lin, Y. C., & Richburg, J. H. (2014). Characterization of the role of tumor necrosis factor apoptosis inducing ligand (TRAIL) in spermatogenesis through the evaluation of trail gene-deficient mice. PLoS One, 9(4), e93926. https://doi.org/10.1371/journal.pone.0093926.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yen, M. L., Hsu, P. N., Liao, H. J., Lee, B. H., & Tsai, H. F. (2012). TRAF-6 dependent signaling pathway is essential for TNF-related apoptosis-inducing ligand (TRAIL) induces osteoclast differentiation. PLoS One, 7(6), e38048. https://doi.org/10.1371/journal.pone.0038048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hameed, A. G., Arnold, N. D., Chamberlain, J., Pickworth, J. A., Paiva, C., Dawson, S., et al. (2012). Inhibition of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) reverses experimental pulmonary hypertension. The Journal of Experimental Medicine, 209(11), 1919–1935. https://doi.org/10.1084/jem.20112716.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Stagg, H. W., Bowen, K. A., Sawant, D. A., Rodriguez, M., Tharakan, B., & Childs, E. W. (2013). Tumor necrosis factor-related apoptosis-inducing ligand promotes microvascular endothelial cell hyperpermeability through phosphatidylinositol 3-kinase pathway. American Journal of Surgery, 205(4), 419–425. https://doi.org/10.1016/j.amjsurg.2012.10.027.

    Article  CAS  PubMed  Google Scholar 

  39. Sokulsky, L. A., Collison, A. M., Nightingale, S., Fevre, A. L., Percival, E., Starkey, M. R., et al. (2016). TRAIL deficiency and PP2A activation with salmeterol ameliorates egg allergen-driven eosinophilic esophagitis. American Journal of Physiology. Gastrointestinal and Liver Physiology, 311(6), G998–G1008. https://doi.org/10.1152/ajpgi.00151.2016.

    Article  PubMed  Google Scholar 

  40. Collison, A., Li, J., Pereira de Siqueira, A., Zhang, J., Toop, H. D., Morris, J. C., et al. (2014). Tumor necrosis factor-related apoptosis-inducing ligand regulates hallmark features of airways remodeling in allergic airways disease. American Journal of Respiratory Cell and Molecular Biology, 51(1), 86–93. https://doi.org/10.1165/rcmb.2013-0490OC.

    Article  CAS  PubMed  Google Scholar 

  41. Arabpour, M., Poelstra, K., Helfrich, W., Bremer, E., & Haisma, H. J. (2014). Targeted elimination of activated hepatic stellate cells by an anti-epidermal growth factor-receptor single chain fragment variable antibody-tumor necrosis factor-related apoptosis-inducing ligand (scFv425-sTRAIL). The Journal of Gene Medicine, 16(9–10), 281–290. https://doi.org/10.1002/jgm.2776.

    Article  CAS  PubMed  Google Scholar 

  42. Peteranderl, C., Morales-Nebreda, L., Selvakumar, B., Lecuona, E., Vadasz, I., Morty, R. E., et al. (2016). Macrophage-epithelial paracrine crosstalk inhibits lung edema clearance during influenza infection. The Journal of Clinical Investigation, 126(4), 1566–1580. https://doi.org/10.1172/JCI83931.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Smith, W., Tomasec, P., Aicheler, R., Loewendorf, A., Nemcovicova, I., Wang, E. C., et al. (2013). Human cytomegalovirus glycoprotein UL141 targets the TRAIL death receptors to thwart host innate antiviral defenses. Cell Host & Microbe, 13(3), 324–335. https://doi.org/10.1016/j.chom.2013.02.003.

    Article  CAS  Google Scholar 

  44. Cantarella, G., Pignataro, G., Di Benedetto, G., Anzilotti, S., Vinciguerra, A., Cuomo, O., et al. (2014). Ischemic tolerance modulates TRAIL expression and its receptors and generates a neuroprotected phenotype. Cell Death & Disease, 5, e1331. https://doi.org/10.1038/cddis.2014.286.

    Article  CAS  Google Scholar 

  45. Kao, S. Y., Soares, V. Y., Kristiansen, A. G., & Stankovic, K. M. (2016). Activation of TRAIL-DR5 pathway promotes sensorineural degeneration in the inner ear. Aging Cell, 15(2), 301–308. https://doi.org/10.1111/acel.12437.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kojima, Y., Nakayama, M., Nishina, T., Nakano, H., Koyanagi, M., Takeda, K., et al. (2011). Importin beta1 protein-mediated nuclear localization of death receptor 5 (DR5) limits DR5/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced cell death of human tumor cells. The Journal of Biological Chemistry, 286(50), 43383–43393. https://doi.org/10.1074/jbc.M111.309377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sun, S. Y., Yue, P., Zhou, J.-Y., Wang, Y., Kim, H. C., Lotan, R., et al. (2001). Overexpression of bcl2 blocks TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human lung cancer cells. Biochemical and Biophysical Research Communications, 280, 788–797.

    Article  CAS  Google Scholar 

  48. Fulda, S., Meyer, E., & Debatin, K. M. (2002). Inhibition of TRAIL-induced apoptosis by Bcl-2 overexpression. Oncogene, 21(15), 2283–2294. https://doi.org/10.1038/sj.onc.1205258.

    Article  CAS  PubMed  Google Scholar 

  49. Hinz, S., Trauzold, A., Boenicke, L., Sandberg, C., Beckmann, S., Bayer, E., et al. (2000). Bcl-XL protects pancreatic adenocarcinoma cells against CD95- and TRAIL-receptor-mediated apoptosis. Oncogene, 19(48), 5477–5486. https://doi.org/10.1038/sj.onc.1203936.

    Article  CAS  PubMed  Google Scholar 

  50. Xu, L., Zhang, Y., Liu, J., Qu, J., Hu, X., Zhang, F., et al. (2012). TRAIL-activated EGFR by Cbl-b-regulated EGFR redistribution in lipid rafts antagonises TRAIL-induced apoptosis in gastric cancer cells. European Journal of Cancer, 48(17), 3288–3299. https://doi.org/10.1016/j.ejca.2012.03.005.

    Article  CAS  PubMed  Google Scholar 

  51. Galski, H., Oved-Gelber, T., Simanovsky, M., Lazarovici, P., Gottesman, M. M., & Nagler, A. (2013). P-glycoprotein-dependent resistance of cancer cells toward the extrinsic TRAIL apoptosis signaling pathway. Biochemical Pharmacology, 86(5), 584–596. https://doi.org/10.1016/j.bcp.2013.06.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Souza, P. S., Madigan, J. P., Gillet, J. P., Kapoor, K., Ambudkar, S. V., Maia, R. C., et al. (2015). Expression of the multidrug transporter P-glycoprotein is inversely related to that of apoptosis-associated endogenous TRAIL. Experimental Cell Research, 336(2), 318–328. https://doi.org/10.1016/j.yexcr.2015.06.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Lemke, J., von Karstedt, S., Abd El Hay, M., Conti, A., Arce, F., Montinaro, A., et al. (2014). Selective CDK9 inhibition overcomes TRAIL resistance by concomitant suppression of cFlip and Mcl-1. Cell Death and Differentiation, 21(3), 491–502. https://doi.org/10.1038/cdd.2013.179.

    Article  CAS  PubMed  Google Scholar 

  54. Rahman, M., Davis, S. R., Pumphrey, J. G., Bao, J., Nau, M. M., Meltzer, P. S., et al. (2009). TRAIL induces apoptosis in triple-negative breast cancer cells with a mesenchymal phenotype. Breast Cancer Research and Treatment, 113(2), 217–230. https://doi.org/10.1007/s10549-008-9924-5.

    Article  PubMed  Google Scholar 

  55. French, R., Hayward, O., Jones, S., Yang, W., & Clarkson, R. (2015). Cytoplasmic levels of cFLIP determine a broad susceptibility of breast cancer stem/progenitor-like cells to TRAIL. Molecular Cancer, 14, 209. https://doi.org/10.1186/s12943-015-0478-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Yerbes, R., Lopez-Rivas, A., Reginato, M. J., & Palacios, C. (2012). Control of FLIP(L) expression and TRAIL resistance by the extracellular signal-regulated kinase1/2 pathway in breast epithelial cells. Cell Death and Differentiation, 19(12), 1908–1916. https://doi.org/10.1038/cdd.2012.78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Li, C., Egloff, A. M., Sen, M., Grandis, J. R., & Johnson, D. E. (2014). Caspase-8 mutations in head and neck cancer confer resistance to death receptor-mediated apoptosis and enhance migration, invasion, and tumor growth. Molecular Oncology, 8(7), 1220–1230. https://doi.org/10.1016/j.molonc.2014.03.018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hong, S., Kim, H. Y., Kim, J., Ha, H. T., Kim, Y. M., Bae, E., et al. (2013). Smad7 protein induces interferon regulatory factor 1-dependent transcriptional activation of caspase 8 to restore tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. The Journal of Biological Chemistry, 288(5), 3560–3570. https://doi.org/10.1074/jbc.M112.400408.

    Article  CAS  PubMed  Google Scholar 

  59. Oya, M., Ohtsubo, M., Takayanagi, A., Tachibana, M., Shimizu, N., & Murai, M. (2001). Constitutive activation of nuclear factor-kappaB prevents TRAIL-induced apoptosis in renal cancer cells. Oncogene, 20(29), 3888–3896. https://doi.org/10.1038/sj.onc.1204525.

    Article  CAS  PubMed  Google Scholar 

  60. Zhang, L., Blackwell, K., Workman, L. M., Chen, S., Pope, M. R., Janz, S., et al. (2015). RIP1 cleavage in the kinase domain regulates TRAIL-induced NF-kappaB activation and lymphoma survival. Molecular and Cellular Biology, 35(19), 3324–3338. https://doi.org/10.1128/MCB.00692-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Takahashi, K., Takeda, K., Saiki, I., Irimura, T., & Hayakawa, Y. (2013). Functional roles of tumor necrosis factor-related apoptosis-inducing ligand-DR5 interaction in B16F10 cells by activating the nuclear factor-kappaB pathway to induce metastatic potential. Cancer Science, 104(5), 558–562. https://doi.org/10.1111/cas.12112.

    Article  CAS  PubMed  Google Scholar 

  62. Somasekharan, S. P., Koc, M., Morizot, A., Micheau, O., Sorensen, P. H., Gaide, O., et al. (2013). TRAIL promotes membrane blebbing, detachment and migration of cells displaying a dysfunctional intrinsic pathway of apoptosis. Apoptosis, 18(3), 324–336. https://doi.org/10.1007/s10495-012-0782-6.

    Article  CAS  PubMed  Google Scholar 

  63. Piggott, L., Omidvar, N., Marti Perez, S., French, R., Eberl, M., & Clarkson, R. W. (2011). Suppression of apoptosis inhibitor c-FLIP selectively eliminates breast cancer stem cell activity in response to the anti-cancer agent, TRAIL. Breast Cancer Research, 13(5), R88. https://doi.org/10.1186/bcr2945.

    Article  CAS  PubMed  Google Scholar 

  64. Ullenhag, G. J., Al-Attar, A., Mukherjee, A., Green, A. R., Ellis, I. O., & Durrant, L. G. (2015). The TRAIL system is over-expressed in breast cancer and FLIP a marker of good prognosis. Journal of Cancer Research and Clinical Oncology, 141(3), 505–514. https://doi.org/10.1007/s00432-014-1822-0.

    Article  CAS  PubMed  Google Scholar 

  65. Yang, M., Liu, L., Xie, M., Sun, X., Yu, Y., Kang, R., et al. (2015). Poly-ADP-ribosylation of HMGB1 regulates TNFSF10/TRAIL resistance through autophagy. Autophagy, 11(2), 214–224. https://doi.org/10.4161/15548627.2014.994400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Narayan, G., Xie, D., Ishdorj, G., Scotto, L., Mansukhani, M., Pothuri, B., et al. (2016). Epigenetic inactivation of TRAIL decoy receptors at 8p12-21.3 commonly deleted region confers sensitivity to Apo2L/trail-cisplatin combination therapy in cervical cancer. Genes, Chromosomes & Cancer, 55(2), 177–189. https://doi.org/10.1002/gcc.22325.

    Article  CAS  Google Scholar 

  67. Romano, G., Acunzo, M., Garofalo, M., Di Leva, G., Cascione, L., Zanca, C., et al. (2012). MiR-494 is regulated by ERK1/2 and modulates TRAIL-induced apoptosis in non-small-cell lung cancer through BIM down-regulation. Proceedings of the National Academy of Sciences of the United States of America, 109(41), 16570–16575. https://doi.org/10.1073/pnas.1207917109.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Iaboni, M., Russo, V., Fontanella, R., Roscigno, G., Fiore, D., Donnarumma, E., et al. (2016). Aptamer-miRNA-212 conjugate sensitizes NSCLC cells to TRAIL. Molecular Therapy-Nucleic Acids, 5, e289. https://doi.org/10.1038/mtna.2016.5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ashkenazi, A., Holland, P., & Eckhardt, S. G. (2008). Ligand-based targeting of apoptosis in cancer: the potential of recombinant human apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL). Journal of Clinical Oncology, 26(21), 3621–3630.

    Article  CAS  Google Scholar 

  70. Leng, Y., Hou, J., Jin, J., Zhang, M., Ke, X., Jiang, B., et al. (2017). Circularly permuted TRAIL plus thalidomide and dexamethasone versus thalidomide and dexamethasone for relapsed/refractory multiple myeloma: a phase 2 study. Cancer Chemotherapy and Pharmacology, 79(6), 1141–1149. https://doi.org/10.1007/s00280-017-3310-0.

    Article  CAS  PubMed  Google Scholar 

  71. Geng, C., Hou, J., Zhao, Y., Ke, X., Wang, Z., Qiu, L., et al. (2014). A multicenter, open-label phase II study of recombinant CPT (circularly permuted TRAIL) plus thalidomide in patients with relapsed and refractory multiple myeloma. American Journal of Hematology, 89(11), 1037–1042. https://doi.org/10.1002/ajh.23822.

    Article  CAS  PubMed  Google Scholar 

  72. Cheah, C. Y., Belada, D., Fanale, M. A., Janikova, A., Czucman, M. S., Flinn, I. W., et al. (2015). Dulanermin with rituximab in patients with relapsed indolent B-cell lymphoma: an open-label phase 1b/2 randomised study. The Lancet. Haematology, 2(4), e166–e174. https://doi.org/10.1016/S2352-3026(15)00026-5.

    Article  PubMed  Google Scholar 

  73. Wainberg, Z. A., Messersmith, W. A., Peddi, P. F., Kapp, A. V., Ashkenazi, A., Royer-Joo, S., et al. (2013). A phase 1B study of dulanermin in combination with modified FOLFOX6 plus bevacizumab in patients with metastatic colorectal cancer. Clinical Colorectal Cancer, 12(4), 248–254. https://doi.org/10.1016/j.clcc.2013.06.002.

    Article  CAS  PubMed  Google Scholar 

  74. Pan, Y., Xu, R., Peach, M., Huang, C. P., Branstetter, D., Novotny, W., et al. (2011). Evaluation of pharmacodynamic biomarkers in a phase 1a trial of dulanermin (rhApo2L/TRAIL) in patients with advanced tumours. British Journal of Cancer, 105(12), 1830–1838. https://doi.org/10.1038/bjc.2011.456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Soria, J. C., Mark, Z., Zatloukal, P., Szima, B., Albert, I., Juhasz, E., et al. (2011). Randomized phase II study of dulanermin in combination with paclitaxel, carboplatin, and bevacizumab in advanced non-small-cell lung cancer. Journal of Clinical Oncology, 29(33), 4442–4451. https://doi.org/10.1200/JCO.2011.37.2623.

    Article  CAS  PubMed  Google Scholar 

  76. Soria, J. C., Smit, E., Khayat, D., Besse, B., Yang, X., Hsu, C. P., et al. (2010). Phase 1b study of dulanermin (recombinant human Apo2L/TRAIL) in combination with paclitaxel, carboplatin, and bevacizumab in patients with advanced non-squamous non-small-cell lung cancer. Journal of Clinical Oncology, 28(9), 1527–1533. https://doi.org/10.1200/JCO.2009.25.4847.

    Article  CAS  PubMed  Google Scholar 

  77. Herbst, R. S., Eckhardt, S. G., Kurzrock, R., Ebbinghaus, S., O'Dwyer, P. J., Gordon, M. S., et al. (2010). Phase I dose-escalation study of recombinant human Apo2L/TRAIL, a dual proapoptotic receptor agonist, in patients with advanced cancer. Journal of Clinical Oncology, 28(17), 2839–2846. https://doi.org/10.1200/JCO.2009.25.1991.

    Article  CAS  PubMed  Google Scholar 

  78. Ciprotti, M., Tebbutt, N. C., Lee, F. T., Lee, S. T., Gan, H. K., McKee, D. C., et al. (2015). Phase I imaging and pharmacodynamic trial of CS-1008 in patients with metastatic colorectal cancer. Journal of Clinical Oncology, 33(24), 2609–2616. https://doi.org/10.1200/JCO.2014.60.4256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Cheng, A. L., Kang, Y. K., He, A. R., Lim, H. Y., Ryoo, B. Y., Hung, C. H., et al. (2015). Safety and efficacy of tigatuzumab plus sorafenib as first-line therapy in subjects with advanced hepatocellular carcinoma: a phase 2 randomized study. Journal of Hepatology, 63(4), 896–904. https://doi.org/10.1016/j.jhep.2015.06.001.

    Article  CAS  PubMed  Google Scholar 

  80. Forero-Torres, A., Varley, K. E., Abramson, V. G., Li, Y., Vaklavas, C., Lin, N. U., et al. (2015). TBCRC 019: a phase II trial of nanoparticle albumin-bound paclitaxel with or without the anti-death receptor 5 monoclonal antibody tigatuzumab in patients with triple-negative breast cancer. Clinical Cancer Research, 21(12), 2722–2729. https://doi.org/10.1158/1078-0432.CCR-14-2780.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Forero-Torres, A., Infante, J. R., Waterhouse, D., Wong, L., Vickers, S., Arrowsmith, E., et al. (2013). Phase 2, multicenter, open-label study of tigatuzumab (CS-1008), a humanized monoclonal antibody targeting death receptor 5, in combination with gemcitabine in chemotherapy-naive patients with unresectable or metastatic pancreatic cancer. Cancer Medicine, 2(6), 925–932. https://doi.org/10.1002/cam4.137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Reck, M., Krzakowski, M., Chmielowska, E., Sebastian, M., Hadler, D., Fox, T., et al. (2013). A randomized, double-blind, placebo-controlled phase 2 study of tigatuzumab (CS-1008) in combination with carboplatin/paclitaxel in patients with chemotherapy-naive metastatic/unresectable non-small cell lung cancer. Lung Cancer, 82(3), 441–448. https://doi.org/10.1016/j.lungcan.2013.09.014.

    Article  PubMed  Google Scholar 

  83. Forero-Torres, A., Shah, J., Wood, T., Posey, J., Carlisle, R., Copigneaux, C., et al. (2010). Phase I trial of weekly tigatuzumab, an agonistic humanized monoclonal antibody targeting death receptor 5 (DR5). Cancer Biotherapy & Radiopharmaceuticals, 25(1), 13–19. https://doi.org/10.1089/cbr.2009.0673.

    Article  CAS  Google Scholar 

  84. Ciuleanu, T., Bazin, I., Lungulescu, D., Miron, L., Bondarenko, I., Deptala, A., et al. (2016). A randomized, double-blind, placebo-controlled phase II study to assess the efficacy and safety of mapatumumab with sorafenib in patients with advanced hepatocellular carcinoma. Annals of Oncology, 27(4), 680–687. https://doi.org/10.1093/annonc/mdw004.

    Article  CAS  PubMed  Google Scholar 

  85. von Pawel, J., Harvey, J. H., Spigel, D. R., Dediu, M., Reck, M., Cebotaru, C. L., et al. (2014). Phase II trial of mapatumumab, a fully human agonist monoclonal antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1), in combination with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer. Clinical Lung Cancer, 15(3), 188–196 e182. https://doi.org/10.1016/j.cllc.2013.12.005.

    Article  CAS  Google Scholar 

  86. Younes, A., Vose, J. M., Zelenetz, A. D., Smith, M. R., Burris, H. A., Ansell, S. M., et al. (2010). A phase 1b/2 trial of mapatumumab in patients with relapsed/refractory non-Hodgkin’s lymphoma. British Journal of Cancer, 103(12), 1783–1787. https://doi.org/10.1038/sj.bjc.6605987.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Trarbach, T., Moehler, M., Heinemann, V., Kohne, C. H., Przyborek, M., Schulz, C., et al. (2010). Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer. British Journal of Cancer, 102(3), 506–512. https://doi.org/10.1038/sj.bjc.6605507.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Mom, C. H., Verweij, J., Oldenhuis, C. N., Gietema, J. A., Fox, N. L., Miceli, R., et al. (2009). Mapatumumab, a fully human agonistic monoclonal antibody that targets TRAIL-R1, in combination with gemcitabine and cisplatin: a phase I study. Clinical Cancer Research, 15(17), 5584–5590. https://doi.org/10.1158/1078-0432.CCR-09-0996.

    Article  CAS  PubMed  Google Scholar 

  89. Hotte, S. J., Hirte, H. W., Chen, E. X., Siu, L. L., Le, L. H., Corey, A., et al. (2008). A phase 1 study of mapatumumab (fully human monoclonal antibody to TRAIL-R1) in patients with advanced solid malignancies. Clinical Cancer Research, 14(11), 3450–3455. https://doi.org/10.1158/1078-0432.CCR-07-1416.

    Article  CAS  PubMed  Google Scholar 

  90. Leong, S., Cohen, R. B., Gustafson, D. L., Langer, C. J., Camidge, D. R., Padavic, K., et al. (2009). Mapatumumab, an antibody targeting TRAIL-R1, in combination with paclitaxel and carboplatin in patients with advanced solid malignancies: results of a phase I and pharmacokinetic study. Journal of Clinical Oncology, 27(26), 4413–4421. https://doi.org/10.1200/JCO.2008.21.7422.

    Article  CAS  PubMed  Google Scholar 

  91. Greco, F. A., Bonomi, P., Crawford, J., Kelly, K., Oh, Y., Halpern, W., et al. (2008). Phase 2 study of mapatumumab, a fully human agonistic monoclonal antibody which targets and activates the TRAIL receptor-1, in patients with advanced non-small cell lung cancer. Lung Cancer, 61(1), 82–90. https://doi.org/10.1016/j.lungcan.2007.12.011.

    Article  PubMed  Google Scholar 

  92. Tolcher, A. W., Mita, M., Meropol, N. J., von Mehren, M., Patnaik, A., Padavic, K., et al. (2007). Phase I pharmacokinetic and biologic correlative study of mapatumumab, a fully human monoclonal antibody with agonist activity to tumor necrosis factor-related apoptosis-inducing ligand receptor-1. Journal of Clinical Oncology, 25(11), 1390–1395. https://doi.org/10.1200/JCO.2006.08.8898.

    Article  CAS  PubMed  Google Scholar 

  93. Paz-Ares, L., Balint, B., de Boer, R. H., van Meerbeeck, J. P., Wierzbicki, R., De Souza, P., et al. (2013). A randomized phase 2 study of paclitaxel and carboplatin with or without conatumumab for first-line treatment of advanced non-small-cell lung cancer. Journal of Thoracic Oncology, 8(3), 329–337. https://doi.org/10.1097/JTO.0b013e31827ce554.

    Article  CAS  PubMed  Google Scholar 

  94. Cohn, A. L., Tabernero, J., Maurel, J., Nowara, E., Sastre, J., Chuah, B. Y., et al. (2013). A randomized, placebo-controlled phase 2 study of ganitumab or conatumumab in combination with FOLFIRI for second-line treatment of mutant KRAS metastatic colorectal cancer. Annals of Oncology, 24(7), 1777–1785. https://doi.org/10.1093/annonc/mdt057.

    Article  CAS  PubMed  Google Scholar 

  95. Fuchs, C. S., Fakih, M., Schwartzberg, L., Cohn, A. L., Yee, L., Dreisbach, L., et al. (2013). TRAIL receptor agonist conatumumab with modified FOLFOX6 plus bevacizumab for first-line treatment of metastatic colorectal cancer: a randomized phase 1b/2 trial. Cancer, 119(24), 4290–4298. https://doi.org/10.1002/cncr.28353.

    Article  CAS  PubMed  Google Scholar 

  96. Kindler, H. L., Richards, D. A., Garbo, L. E., Garon, E. B., Stephenson Jr., J. J., Rocha-Lima, C. M., et al. (2012). A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer. Annals of Oncology, 23(11), 2834–2842. https://doi.org/10.1093/annonc/mds142.

    Article  CAS  PubMed  Google Scholar 

  97. Demetri, G. D., Le Cesne, A., Chawla, S. P., Brodowicz, T., Maki, R. G., Bach, B. A., et al. (2012). First-line treatment of metastatic or locally advanced unresectable soft tissue sarcomas with conatumumab in combination with doxorubicin or doxorubicin alone: a phase I/II open-label and double-blind study. European Journal of Cancer, 48(4), 547–563. https://doi.org/10.1016/j.ejca.2011.12.008.

    Article  CAS  PubMed  Google Scholar 

  98. Doi, T., Murakami, H., Ohtsu, A., Fuse, N., Yoshino, T., Yamamoto, N., et al. (2011). Phase 1 study of conatumumab, a pro-apoptotic death receptor 5 agonist antibody, in Japanese patients with advanced solid tumors. Cancer Chemotherapy and Pharmacology, 68(3), 733–741. https://doi.org/10.1007/s00280-010-1544-1.

    Article  CAS  PubMed  Google Scholar 

  99. Herbst, R. S., Kurzrock, R., Hong, D. S., Valdivieso, M., Hsu, C. P., Goyal, L., et al. (2010). A first-in-human study of conatumumab in adult patients with advanced solid tumors. Clinical Cancer Research, 16(23), 5883–5891. https://doi.org/10.1158/1078-0432.CCR-10-0631.

    Article  CAS  PubMed  Google Scholar 

  100. Papadopoulos, K. P., Isaacs, R., Bilic, S., Kentsch, K., Huet, H. A., Hofmann, M., et al. (2015). Unexpected hepatotoxicity in a phase I study of TAS266, a novel tetravalent agonistic Nanobody(R) targeting the DR5 receptor. Cancer Chemotherapy and Pharmacology, 75(5), 887–895. https://doi.org/10.1007/s00280-015-2712-0.

    Article  CAS  PubMed  Google Scholar 

  101. Arrillaga-Romany, I., Chi, A. S., Allen, J. E., Oster, W., Wen, P. Y., & Batchelor, T. T. (2017). A phase 2 study of the first imipridone ONC201, a selective DRD2 antagonist for oncology, administered every three weeks in recurrent glioblastoma. Oncotarget, 8(45), 79298–79304. https://doi.org/10.18632/oncotarget.17837.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Stein, M. N., Bertino, J. R., Kaufman, H. L., Mayer, T., Moss, R., Silk, A., et al. (2017). First-in-human clinical trial of oral ONC201 in patients with refractory solid tumors. Clinical Cancer Research, 23(15), 4163–4169. https://doi.org/10.1158/1078-0432.CCR-16-2658.

    Article  CAS  PubMed  Google Scholar 

  103. Soria, J., Smit, E. F., Khayat, D., Besse, B., Burton, J., Yang, X., et al. (2008). Phase Ib study of recombinant human (rh) Apo2L/TRAIL in combination with paclitaxel, carboplatin, and bevacizumab (PCB) in patients with advanced non-small cell lung cancer (NSCLC). Journal of Clinical Oncology, 26(No 15S (May 20 Supplement)), 3539.

  104. Subbiah, V., Brown, R. E., Buryanek, J., Trent, J., Ashkenazi, A., Herbst, R., et al. (2012). Targeting the apoptotic pathway in chondrosarcoma using recombinant human Apo2L/TRAIL (dulanermin), a dual proapoptotic receptor (DR4/DR5) agonist. Molecular Cancer Therapeutics, 11(11), 2541–2546. https://doi.org/10.1158/1535-7163.MCT-12-0358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. von Karstedt, S., Montinaro, A., & Walczak, H. (2017). Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nature Reviews. Cancer, 17(6), 352–366. https://doi.org/10.1038/nrc.2017.28.

    Article  CAS  Google Scholar 

  106. Ichikawa, K., Liu, W., Zhao, L., Wang, Z., Liu, D., Ohtsuka, T., et al. (2001). Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity. Nature Medicine, 7(8), 954–960.

    Article  CAS  Google Scholar 

  107. Zhang, L., Zhang, X., Barrisford, G. W., & Olumi, A. F. (2007). Lexatumumab (TRAIL-receptor 2 mAb) induces expression of DR5 and promotes apoptosis in primary and metastatic renal cell carcinoma in a mouse orthotopic model. Cancer Letters, 251(1), 146–157. https://doi.org/10.1016/j.canlet.2006.11.013.

    Article  CAS  PubMed  Google Scholar 

  108. Malin, D., Chen, F., Schiller, C., Koblinski, J., & Cryns, V. L. (2011). Enhanced metastasis suppression by targeting TRAIL receptor 2 in a murine model of triple-negative breast cancer. [Research support, non-U.S. Gov’t]. Clinical Cancer Research, 17(15), 5005–5015. https://doi.org/10.1158/1078-0432.CCR-11-0099.

    Article  CAS  PubMed  Google Scholar 

  109. Gieffers, C., Kluge, M., Merz, C., Sykora, J., Thiemann, M., Schaal, R., et al. (2013). APG350 induces superior clustering of TRAIL receptors and shows therapeutic antitumor efficacy independent of cross-linking via Fcgamma receptors. Molecular Cancer Therapeutics, 12(12), 2735–2747. https://doi.org/10.1158/1535-7163.MCT-13-0323.

    Article  CAS  PubMed  Google Scholar 

  110. Kagawa, S., He, C., Gu, J., Koch, P., Rha, S. J., Roth, J. A., et al. (2001). Antitumor activity and bystander effects of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene. Cancer Research, 61(8), 3330–3338.

    CAS  PubMed  Google Scholar 

  111. Kim, S. Y., Lee, D. H., Song, X., Bartlett, D. L., Kwon, Y. T., & Lee, Y. J. (2014). Role of Bcl-xL/Beclin-1 in synergistic apoptotic effects of secretory TRAIL-armed adenovirus in combination with mitomycin C and hyperthermia on colon cancer cells. Apoptosis, 19(11), 1603–1615. https://doi.org/10.1007/s10495-014-1028-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Spitzer, D., McDunn, J. E., Plambeck-Suess, S., Goedegebuure, P. S., Hotchkiss, R. S., & Hawkins, W. G. (2010). A genetically encoded multifunctional TRAIL trimer facilitates cell-specific targeting and tumor cell killing. Molecular Cancer Therapeutics, 9(7), 2142–2151. https://doi.org/10.1158/1535-7163.MCT-10-0225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Garg, G., Gibbs, J., Belt, B., Powell, M. A., Mutch, D. G., Goedegebuure, P., et al. (2014). Novel treatment option for MUC16-positive malignancies with the targeted TRAIL-based fusion protein Meso-TR3. BMC Cancer, 14, 35. https://doi.org/10.1186/1471-2407-14-35.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Perlstein, B., Finniss, S. A., Miller, C., Okhrimenko, H., Kazimirsky, G., Cazacu, S., et al. (2013). TRAIL conjugated to nanoparticles exhibits increased anti-tumor activities in glioma cells and glioma stem cells in vitro and in vivo. Neuro-Oncology, 15(1), 29–40. https://doi.org/10.1093/neuonc/nos248.

    Article  CAS  PubMed  Google Scholar 

  115. Piechocki, M. P., Wu, G. S., Jones, R. F., Jacob, J. B., Gibson, H., Ethier, S. P., et al. (2012). Induction of proapoptotic antibodies to triple-negative breast cancer by vaccination with TRAIL death receptor DR5 DNA. International Journal of Cancer. https://doi.org/10.1002/ijc.27534.

  116. Ding, B., Wu, X., Fan, W., Wu, Z., Gao, J., Zhang, W., et al. (2011). Anti-DR5 monoclonal antibody-mediated DTIC-loaded nanoparticles combining chemotherapy and immunotherapy for malignant melanoma: target formulation development and in vitro anticancer activity. International Journal of Nanomedicine, 6, 1991–2005. https://doi.org/10.2147/IJN.S24094.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Wu, G. S., Burns, T. F., McDonald, E. R., Jiang, W., Meng, R., Krantz, I. D., et al. (1997). KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nature Genetics, 17, 141–143.

    Article  CAS  Google Scholar 

  118. Ding, L., Yuan, C., Wei, F., Wang, G., Zhang, J., Bellail, A. C., et al. (2011). Cisplatin restores TRAIL apoptotic pathway in glioblastoma-derived stem cells through up-regulation of DR5 and down-regulation of c-FLIP. Cancer Investigation, 29(8), 511–520. https://doi.org/10.3109/07357907.2011.605412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Jelinkova, I., Safarikova, B., Vondalova Blanarova, O., Skender, B., Hofmanova, J., Sova, P., et al. (2014). Platinum(IV) complex LA-12 exerts higher ability than cisplatin to enhance TRAIL-induced cancer cell apoptosis via stimulation of mitochondrial pathway. Biochemical Pharmacology, 92(3), 415–424. https://doi.org/10.1016/j.bcp.2014.09.013.

    Article  CAS  PubMed  Google Scholar 

  120. Pasello, G., Urso, L., Silic-Benussi, M., Schiavon, M., Cavallari, I., Marulli, G., et al. (2014). Synergistic antitumor activity of recombinant human Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in combination with carboplatin and pemetrexed in malignant pleural mesothelioma. Journal of Thoracic Oncology, 9(7), 1008–1017. https://doi.org/10.1097/JTO.0000000000000198.

    Article  CAS  PubMed  Google Scholar 

  121. Sung, E. S., Kim, A., Park, J. S., Chung, J., Kwon, M. H., & Kim, Y. S. (2010). Histone deacetylase inhibitors synergistically potentiate death receptor 4-mediated apoptotic cell death of human T-cell acute lymphoblastic leukemia cells. Apoptosis, 15(10), 1256–1269. https://doi.org/10.1007/s10495-010-0521-9.

    Article  CAS  PubMed  Google Scholar 

  122. Nakata, S., Yoshida, T., Horinaka, M., Shiraishi, T., Wakada, M., & Sakai, T. (2004). Histone deacetylase inhibitors upregulate death receptor 5/TRAIL-R2 and sensitize apoptosis induced by TRAIL/APO2-L in human malignant tumor cells. Oncogene, 23(37), 6261–6271.

    Article  CAS  Google Scholar 

  123. He, L., Jang, J. H., Choi, H. G., Lee, S. M., Nan, M. H., Jeong, S. J., et al. (2013). Oligomycin A enhances apoptotic effect of TRAIL through CHOP-mediated death receptor 5 expression. Molecular Carcinogenesis, 52(2), 85–93. https://doi.org/10.1002/mc.21831.

    Article  CAS  PubMed  Google Scholar 

  124. Liu, Y., Tong, Y., Yang, X., Li, F., Zheng, L., Liu, W., et al. (2016). Novel histone deacetylase inhibitors derived from Magnolia officinalis significantly enhance TRAIL-induced apoptosis in non-small cell lung cancer. Pharmacological Research, 111, 113–125. https://doi.org/10.1016/j.phrs.2016.05.028.

    Article  CAS  PubMed  Google Scholar 

  125. Yang, J., Qian, S., Cai, X., Lu, W., Hu, C., Sun, X., et al. (2016). Chikusetsusaponin IVa butyl ester (CS-IVa-Be), a novel IL6R antagonist, inhibits IL6/STAT3 signaling pathway and induces cancer cell apoptosis. Molecular Cancer Therapeutics, 15(6), 1190–1200. https://doi.org/10.1158/1535-7163.MCT-15-0551.

    Article  CAS  PubMed  Google Scholar 

  126. Kim, J. H., Park, B., Gupta, S. C., Kannappan, R., Sung, B., & Aggarwal, B. B. (2012). Zyflamend sensitizes tumor cells to TRAIL-induced apoptosis through up-regulation of death receptors and down-regulation of survival proteins: role of ROS-dependent CCAAT/enhancer-binding protein-homologous protein pathway. Antioxidants & Redox Signaling, 16(5), 413–427. https://doi.org/10.1089/ars.2011.3982.

    Article  CAS  Google Scholar 

  127. Trivedi, R., Maurya, R., & Mishra, D. P. (2014). Medicarpin, a legume phytoalexin sensitizes myeloid leukemia cells to TRAIL-induced apoptosis through the induction of DR5 and activation of the ROS-JNK-CHOP pathway. Cell Death & Disease, 5, e1465. https://doi.org/10.1038/cddis.2014.429.

    Article  CAS  Google Scholar 

  128. Chen, W., Wang, X., Zhuang, J., Zhang, L., & Lin, Y. (2007). Induction of death receptor 5 and suppression of survivin contribute to sensitization of TRAIL-induced cytotoxicity by quercetin in non-small cell lung cancer cells. Carcinogenesis, 28(10), 2114–2121. https://doi.org/10.1093/carcin/bgm133.

    Article  CAS  PubMed  Google Scholar 

  129. Carter, B. Z., Mak, D. H., Schober, W. D., McQueen, T., Harris, D., Estrov, Z., et al. (2006). Triptolide induces caspase-dependent cell death mediated via the mitochondrial pathway in leukemic cells. Blood, 108(2), 630–637.

    Article  CAS  Google Scholar 

  130. Ding, J., Polier, G., Kohler, R., Giaisi, M., Krammer, P. H., & Li-Weber, M. (2012). Wogonin and related natural flavones overcome tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein resistance of tumors by down-regulation of c-FLIP protein and up-regulation of TRAIL receptor 2 expression. The Journal of Biological Chemistry, 287(1), 641–649. https://doi.org/10.1074/jbc.M111.286526.

    Article  CAS  PubMed  Google Scholar 

  131. Hori, T., Kondo, T., Kanamori, M., Tabuchi, Y., Ogawa, R., Zhao, Q. L., et al. (2010). Nutlin-3 enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through up-regulation of death receptor 5 (DR5) in human sarcoma HOS cells and human colon cancer HCT116 cells. Cancer Letters, 287(1), 98–108. https://doi.org/10.1016/j.canlet.2009.06.002.

    Article  CAS  PubMed  Google Scholar 

  132. Lim, S. C., Parajuli, K. R., & Han, S. I. (2016). The alkyllysophospholipid edelfosine enhances TRAIL-mediated apoptosis in gastric cancer cells through death receptor 5 and the mitochondrial pathway. Tumour Biology, 37(5), 6205–6216. https://doi.org/10.1007/s13277-015-4485-9.

    Article  CAS  PubMed  Google Scholar 

  133. Fassl, A., Tagscherer, K. E., Richter, J., De-Castro Arce, J., Savini, C., Rosl, F., et al. (2015). Inhibition of Notch1 signaling overcomes resistance to the death ligand TRAIL by specificity protein 1-dependent upregulation of death receptor 5. Cell Death & Disease, 6, e1921. https://doi.org/10.1038/cddis.2015.261.

    Article  CAS  Google Scholar 

  134. Lee, D. H., Sung, K. S., Bartlett, D. L., Kwon, Y. T., & Lee, Y. J. (2015). HSP90 inhibitor NVP-AUY922 enhances TRAIL-induced apoptosis by suppressing the JAK2-STAT3-Mcl-1 signal transduction pathway in colorectal cancer cells. Cellular Signalling, 27(2), 293–305. https://doi.org/10.1016/j.cellsig.2014.11.013.

    Article  CAS  PubMed  Google Scholar 

  135. Sung, B., Prasad, S., Ravindran, J., Yadav, V. R., & Aggarwal, B. B. (2012). Capsazepine, a TRPV1 antagonist, sensitizes colorectal cancer cells to apoptosis by TRAIL through ROS-JNK-CHOP-mediated upregulation of death receptors. Free Radical Biology & Medicine, 53(10), 1977–1987. https://doi.org/10.1016/j.freeradbiomed.2012.08.012.

    Article  CAS  Google Scholar 

  136. Kim, H. B., Kim, M. J., Lee, S. H., Lee, J. W., Bae, J. H., Kim, D. W., et al. (2012). Amurensin G, a novel SIRT1 inhibitor, sensitizes TRAIL-resistant human leukemic K562 cells to TRAIL-induced apoptosis. Biochemical Pharmacology, 84(3), 402–410. https://doi.org/10.1016/j.bcp.2012.03.014.

    Article  CAS  PubMed  Google Scholar 

  137. Yang, J., Yang, C., Zhang, S., Mei, Z., Shi, M., Sun, S., et al. (2015). ABC294640, a sphingosine kinase 2 inhibitor, enhances the antitumor effects of TRAIL in non-small cell lung cancer. Cancer Biology & Therapy, 16(8), 1194–1204. https://doi.org/10.1080/15384047.2015.1056944.

    Article  CAS  Google Scholar 

  138. Allen, J. E., Krigsfeld, G., Mayes, P. A., Patel, L., Dicker, D. T., Patel, A. S., et al. (2013). Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects. Sci Transl Med, 5(171), 171ra117. https://doi.org/10.1126/scitranslmed.3004828.

    Article  CAS  Google Scholar 

  139. Kline, C. L., Van den Heuvel, A. P., Allen, J. E., Prabhu, V. V., Dicker, D. T., & El-Deiry, W. S. (2016). ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2alpha kinases. Sci Signal, 9(415), ra18. https://doi.org/10.1126/scisignal.aac4374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Ishizawa, J., Kojima, K., Chachad, D., Ruvolo, P., Ruvolo, V., Jacamo, R. O., et al. (2016). ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies. Sci Signal, 9(415), ra17. https://doi.org/10.1126/scisignal.aac4380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Nagane, M., Pan, G., Weddle, J. J., Dixit, V. M., Cavenee, W. K., & Huang, H. J. (2000). Increased death receptor 5 expression by chemotherapeutic agents in human gliomas causes synergistic cytotoxicity with tumor necrosis factor-related apoptosis-inducing ligand in vitro and in vivo. Cancer Research, 60(4), 847–853.

    CAS  PubMed  Google Scholar 

  142. Wu, X. X., Kakehi, Y., Mizutani, Y., Nishiyama, H., Kamoto, T., Megumi, Y., et al. (2003). Enhancement of TRAIL/Apo2L-mediated apoptosis by adriamycin through inducing DR4 and DR5 in renal cell carcinoma cells. International Journal of Cancer, 104(4), 409–417. https://doi.org/10.1002/ijc.10948.

    Article  CAS  PubMed  Google Scholar 

  143. Gibson, S. B., Oyer, R., Spalding, A. C., Anderson, S. M., & Johnson, G. L. (2000). Increased expression of death receptors 4 and 5 synergizes the apoptosis response to combined treatment with etoposide and TRAIL. Molecular and Cellular Biology, 20(1), 205–212.

    Article  CAS  Google Scholar 

  144. Naka, T., Sugamura, K., Hylander, B. L., Widmer, M. B., Rustum, Y. M., & Repasky, E. A. (2002). Effects of tumor necrosis factor-related apoptosis-inducing ligand alone and in combination with chemotherapeutic agents on patients’ colon tumors grown in SCID mice. Cancer Research, 62(20), 5800–5806.

    CAS  PubMed  Google Scholar 

  145. Wang, S., & El-Deiry, W. S. (2004). Inducible silencing of KILLER/DR5 in vivo promotes bioluminescent colon tumor xenograft growth and confers resistance to chemotherapeutic agent 5-fluorouracil. Cancer Research, 64(18), 6666–6672. https://doi.org/10.1158/0008-5472.CAN-04-1734.

    Article  CAS  PubMed  Google Scholar 

  146. Cheng, H., Hong, B., Zhou, L., Allen, J. E., Tai, G., Humphreys, R., et al. (2012). Mitomycin C potentiates TRAIL-induced apoptosis through p53-independent upregulation of death receptors: evidence for the role of c-Jun N-terminal kinase activation. Cell Cycle, 11(17), 3312–3323. https://doi.org/10.4161/cc.21670.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Senbabaoglu, F., Cingoz, A., Kaya, E., Kazancioglu, S., Lack, N. A., Acilan, C., et al. (2016). Identification of mitoxantrone as a TRAIL-sensitizing agent for glioblastoma multiforme. Cancer Biology & Therapy, 17(5), 546–557. https://doi.org/10.1080/15384047.2016.1167292.

    Article  CAS  Google Scholar 

  148. Zhuang, H., Jiang, W., Zhang, X., Qiu, F., Gan, Z., Cheng, W., et al. (2013). Suppression of HSP70 expression sensitizes NSCLC cell lines to TRAIL-induced apoptosis by upregulating DR4 and DR5 and downregulating c-FLIP-L expressions. Journal of Molecular Medicine (Berlin, Germany), 91(2), 219–235. https://doi.org/10.1007/s00109-012-0947-3.

    Article  CAS  Google Scholar 

  149. Chen, L., Meng, Y., Sun, Q., Zhang, Z., Guo, X., Sheng, X., et al. (2016). Ginsenoside compound K sensitizes human colon cancer cells to TRAIL-induced apoptosis via autophagy-dependent and -independent DR5 upregulation. Cell Death & Disease, 7(8), e2334. https://doi.org/10.1038/cddis.2016.234.

    Article  CAS  Google Scholar 

  150. Allen, J. E., & El-Deiry, W. S. (2012). Regulation of the human TRAIL gene. Cancer Biology & Therapy, 13(12), 1143–1151. https://doi.org/10.4161/cbt.21354.

    Article  CAS  Google Scholar 

  151. Altucci, L., Rossin, A., Raffelsberger, W., Reitmair, A., Chomienne, C., & Gronemeyer, H. (2001). Retinoic acid-induced apoptosis in leukemia cells is mediated by paracrine action of tumor-selective death ligand TRAIL. Nature Medicine, 7(6), 680–686.

    Article  CAS  Google Scholar 

  152. Nebbioso, A., Clarke, N., Voltz, E., Germain, E., Ambrosino, C., Bontempo, P., et al. (2005). Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells. Nature Medicine, 11, 77–84.

    Article  CAS  Google Scholar 

  153. Xu, J., Zhou, J. Y., & Wu, G. S. (2006). Tumor necrosis factor-related apoptosis-inducing ligand is required for tumor necrosis factor {alpha}-mediated sensitization of human breast cancer cells to chemotherapy. Cancer Research, 66(20), 10092–10099.

    Article  CAS  Google Scholar 

  154. Xu, J., Zhou, J. Y., Tainsky, M. A., & Wu, G. S. (2007). Evidence that tumor necrosis factor-related apoptosis-inducing ligand induction by 5-aza-2′-deoxycytidine sensitizes human breast cancer cells to adriamycin. Cancer Research, 67(3), 1203–1211.

    Article  CAS  Google Scholar 

  155. Xu, J., Zhou, J. Y., Wei, W. Z., Philipsen, S., & Wu, G. S. (2008). Sp1-mediated TRAIL induction in chemosensitization. Cancer Research, 68(16), 6718–6726.

    Article  CAS  Google Scholar 

  156. Kuribayashi, K., Krigsfeld, G., Wang, W., Xu, J., Mayes, P. A., Dicker, D. T., et al. (2008). TNFSF10 (TRAIL), a p53 target gene that mediates p53-dependent cell death. Cancer Biology & Therapy, 7(12).

  157. Allen, J. E., Kline, C. L., Prabhu, V. V., Wagner, J., Ishizawa, J., Madhukar, N., et al. (2016). Discovery and clinical introduction of first-in-class imipridone ONC201. Oncotarget, 7(45), 74380–74392. https://doi.org/10.18632/oncotarget.11814.

    Article  PubMed  PubMed Central  Google Scholar 

  158. Prabhu, V. V., Allen, J. E., Dicker, D. T., & El-Deiry, W. S. (2015). Small-molecule ONC201/TIC10 targets chemotherapy-resistant colorectal cancer stem-like cells in an Akt/Foxo3a/TRAIL-dependent manner. Cancer Research, 75(7), 1423–1432. https://doi.org/10.1158/0008-5472.CAN-13-3451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Yuan, X., Kho, D., Xu, J., Gajan, A., Wu, K., & Wu, G. S. (2017). ONC201 activates ER stress to inhibit the growth of triple-negative breast cancer cells. Oncotarget, 8(13), 21626–21638. https://doi.org/10.18632/oncotarget.15451.

    Article  PubMed  PubMed Central  Google Scholar 

  160. Kline, C. L. B., Ralff, M. D., Lulla, A. R., Wagner, J. M., Abbosh, P. H., Dicker, D. T., et al. (2017). Role of dopamine receptors in the anticancer activity of ONC201. Neoplasia, 20(1), 80–91. https://doi.org/10.1016/j.neo.2017.10.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Trauzold, A., Wermann, H., Arlt, A., Schutze, S., Schafer, H., Oestern, S., et al. (2001). CD95 and TRAIL receptor-mediated activation of protein kinase C and NF-kappaB contributes to apoptosis resistance in ductal pancreatic adenocarcinoma cells. Oncogene, 20(31), 4258–4269.

    Article  CAS  Google Scholar 

  162. Trauzold, A., Siegmund, D., Schniewind, B., Sipos, B., Egberts, J., Zorenkov, D., et al. (2006). TRAIL promotes metastasis of human pancreatic ductal adenocarcinoma. Oncogene, 25(56), 7434–7439.

    Article  CAS  Google Scholar 

  163. Xu, J., Zhou, J. Y., Wei, W. Z., & Wu, G. S. (2010). Activation of the Akt survival pathway contributes to TRAIL resistance in cancer cells. PLoS One, 5(4), e10226. https://doi.org/10.1371/journal.pone.0010226.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Hartwig, T., Montinaro, A., von Karstedt, S., Sevko, A., Surinova, S., Chakravarthy, A., et al. (2017). The TRAIL-induced cancer secretome promotes a tumor-supportive immune microenvironment via CCR2. Molecular Cell, 65(4), 730–742 e735. https://doi.org/10.1016/j.molcel.2017.01.021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by NIH grant R01 CA174949 to G.S.W., Natural Science Foundation of China #81572608 to K.W., and Wuhan Science and Technology Bureau #2017060201010170 to K.W.

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Authors and Affiliations

  1. Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People’s Republic of China

    Xun Yuan, Qian Chu, Hua Xiong & Kongming Wu

  2. Departments of Oncology and Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Xun Yuan, Ambikai Gajan & Gen Sheng Wu

  3. Molecular Therapeutics Program, Karmanos Cancer Institute, Departments of Oncology and Pathology, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Gen Sheng Wu

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  1. Xun Yuan
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  2. Ambikai Gajan
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  4. Hua Xiong
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  5. Kongming Wu
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Kongming Wu and Gen Sheng Wu share senior authorship.

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Yuan, X., Gajan, A., Chu, Q. et al. Developing TRAIL/TRAIL death receptor-based cancer therapies. Cancer Metastasis Rev 37, 733–748 (2018). https://doi.org/10.1007/s10555-018-9728-y

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