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Antitumor agent parthenolide reverses resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand through sustained activation of c-Jun N-terminal kinase

Oncogene volume 23, pages 7330–7344 (2004)Cite this article

Abstract

The antitumor activity of the sesquiterpene lactone parthenolide, an active ingredient of medicinal plants, is believed to be due to the inhibition of DNA binding of transcription factors NF-κB and STAT-3, reduction in MAP kinase activity and the generation of reactive oxygen. In this report, we show that parthenolide activates c-Jun N-terminal kinase (JNK), which is independent of inhibition of NF-κB DNA binding and generation of reactive oxygen species. Parthenolide reversed resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Cancer cells treated with a combination of TRAIL and parthenolide underwent massive typical apoptosis and atypical apoptosis involving the loss of plasma membrane integrity. JNK activity is necessary for the parthenolide-induced sensitization to TRAIL because a dominant-negative JNK or the JNK inhibitor SP600125 reduced TRAIL plus parthenolide-induced apoptosis. Parthenolide induced phosphorylation of Bid and increased TRAIL-dependent cleavage of Bid without affecting caspase 8 activities. Cytochrome c but not Smac/DIABLO was released from the mitochondria in cells treated with parthenolide alone. Parthenolide through JNK increased the TRAIL-mediated degradation of the antiapoptotic protein X-linked inhibitor of apoptosis (XIAP). Enhanced XIAP cleavage correlated with increased and prolonged caspase 3 activity and PARP cleavage, suggesting that the sensitization to TRAIL involves ‘feed forward’ activation of caspase 3. These results identify a new antitumor activity of parthenolide, which can be exploited to reverse resistance of cancer cells to TRAIL, particularly those with elevated XIAP levels.

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Abbreviations

TRAIL:

tumor necrosis factor-related apoptosis-inducing ligand

JNK:

c-Jun N-terminal kinase

PARP:

poly(ADP-ribose) polymerase

Z-VAD-FMK:

N-tert-butoxy-carbonyl-Val-Ala-Asp-fluromethyl-ketone

NF-κB:

nuclear factor kappaB

EMSA:

electrophoretic mobility shift assay

XIAP:

X-linked inhibitor of apoptosis protein

Smac:

second mitochondria-derived activator of caspases

MTS, (3-(4:

5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium

References

  • Baldwin AS . (2001). J. Clin. Invest., 107, 241–246.

  • Beg AA and Baltimore D . (1996). Science, 274, 782–784.

  • Berman PA and Adams PA . (1997). Free Radic. Biol. Med., 22, 1283–1288.

  • Bernard D, Quatannens B, Vandenbunder B and Abbadie C . (2001). J. Biol. Chem., 276, 27322–27328.

  • Berns EM, Foekens JA, Vossen R, Look MP, Devilee P, Henzen-Logmans SC, van Staveren IL, van Putten WL, Inganas M, Meijer-van Gelder ME, Cornelisse C, Claassen CJ, Portengen H, Bakker B and Klijn JG . (2000). Cancer Res., 60, 2155–2162.

  • Bhat-Nakshatri P, Newton TR, Goulet Jr R and Nakshatri H . (1998). Proc. Natl. Acad. Sci. USA, 95, 6971–6976.

  • Biswas DK, Cruz AP, Gansberger E and Pardee AB . (2000). Proc. Natl. Acad. Sci. USA, 97, 8542–8547.

  • Bratton SB and Cohen GM . (2003). Cell Death Differ., 10, 4–6.

  • Bykov VJ, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P, Bergman J, Wiman KG and Selivanova G . (2002). Nat. Med., 8, 282–288.

  • Chauhan D, Li G, Hideshima T, Podar K, Mitsiades C, Mitsiades N, Munshi N, Kharbanda S and Anderson KC . (2003). J. Biol. Chem., 278, 17593–17596.

  • Chinnaiyan AM, Prasad U, Shankar S, Hamstra DA, Shanaiah M, Chenevert TL, Ross BD and Rehemtulla A . (2000). Proc. Natl. Acad. Sci. USA, 97, 1754–1759.

  • Daniel PT, Wieder T, Sturm I and Schulze-Osthoff K . (2001). Leukemia, 15, 1022–1032.

  • Davis RJ . (2000). Cell, 103, 239–252.

  • De Smaele E, Zazzeroni F, Papa S, Nguyen DU, Jin R, Jones J, Cong R and Franzoso G . (2001). Nature, 414, 308–313.

  • Deng Y, Ren X, Yang L, Lin Y and Wu X . (2003). Cell, 115, 61–70.

  • Desagher S, Osen-Sand A, Montessuit S, Magnenat E, Vilbois F, Hochmann A, Journot L, Antonsson B and Martinou JC . (2001). Mol. Cell., 8, 601–611.

  • Deveraux QL, Leo E, Stennicke HR, Welsh K, Salvesen GS and Reed JC . (1999). EMBO J., 18, 5242–5251.

  • Eid MA, Lewis RW, Abdel-Mageed AB and Kumar MV . (2002). Int. J. Oncol., 21, 111–117.

  • Hehner SP, Heinrich M, Bork PM, Vogt M, Ratter F, Lehmann V, Schulze-Osthoff K, Dröge W and Schmitz ML . (1998). J. Biol. Chem., 273, 1288–1297.

  • Hehner SP, Hofmann TG, Droge W and Schmitz ML . (1999). J. Immunol., 163, 5617–5623.

  • Hell K, Saleh M, Crescenzo GD, O’Connor-McCourt MD and Nicholson DW . (2003). Cell Death Differ., 10, 1234–1239.

  • Herr I, Wilhelm D, Meyer E, Jeremias I, Angel P and Debatin KM . (1999). Cell Death Differ., 6, 130–135.

  • Javelaud D and Besancon F . (2001). Oncogene, 20, 4365–4372.

  • Johnstone RW, Ruefli AA and Lowe SW . (2002). Cell, 108, 153–164.

  • Karin M, Cao Y, Greten FR and Li ZW . (2002). Nat. Rev. Cancer, 2, 301–310.

  • Kennedy NJ and Davis RJ . (2003). Cell Cycle, 2, 199–201.

  • Kim EH, Kim SU, Shin DY and Choi KS . (2004). Oncogene, 23, 446–456.

  • Lamb JA, Ventura JJ, Hess P, Flavell RA and Davis RJ . (2003). Mol. Cell, 11, 1479–1489.

  • Lawrence D, Shahrokh Z, Marsters S, Achilles K, Shih D, Mounho B, Hillan K, Totpal K, DeForge L, Schow P, Hooley J, Sherwood S, Pai R, Leung S, Khan L, Gliniak B, Bussiere J, Smith CA, Strom SS, Kelley S, Fox JA, Thomas D and Ashkenazi A . (2001). Nat. Med., 7, 383–385.

  • LeBlanc HN and Ashkenazi A . (2003). Cell. Death Differ., 10, 66–75.

  • Lei K and Davis RJ . (2003). Proc. Natl. Acad. Sci. USA, 100, 2432–2437.

  • Lin A . (2003). Bioessays, 25, 17–24.

  • Luo X, Budihardjo I, Zou H, Slaughter C and Wang X . (1998). Cell, 94, 481–490.

  • Martins LM, Turk BE, Cowling V, Borg A, Jarrell ET, Cantley LC and Downward J . (2003). J. Biol. Chem., 278, 49417–49427.

  • Nakshatri H, Bhat-Nakshatri P, Martin DA, Goulet Jr RJ and Sledge Jr GW . (1997). Mol. Cell Biol., 17, 3629–3639.

  • Nakshatri H and Goulet Jr RJ . (2002). Curr. Probl. Cancer, 26, 282–309.

  • Newton TR, Patel NM, Bhat-Nakshatri P, Stauss CR, Goulet Jr RJ and Nakshatri H . (1999). J. Biol. Chem., 274, 18827–18835.

  • Ng CP, Zisman A and Bonavida B . (2002). Prostate, 53, 286–299.

  • Nicholson RI, Hutcheson IR, Harper ME, Knowlden JM, Barrow D, McClelland RA, Jones HE, Wakeling AE and Gee JM . (2001). Endocr. Relat. Cancer, 8, 175–182.

  • Nozaki S, Sledge Jr GW and Nakshatri H . (2000). Biochem. Biophys. Res. Commun., 275, 60–62.

  • Ozoren N and El-Deiry WS . (2003). Semin. Cancer Biol., 13, 135–147.

  • Patel NM, Nozaki S, Shortle NH, Bhat-Nakshatri P, Newton TR, Rice S, Gelfanov V, Boswell SH, Goulet Jr RJ, Sledge Jr GW and Nakshatri H . (2000). Oncogene, 19, 4159–4169.

  • Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K and Cobb MH . (2001). Endocr. Rev., 22, 153–183.

  • Pozarowski P, Halicka DH and Darzynkiewicz Z . (2003a). Cell Cycle, 2, 377–383.

  • Pozarowski P, Halicka DH and Darzynkiewicz Z . (2003b). Cytometry., 54A, 118–124.

  • Reuther-Madrid JY, Kashatus D, Chen S, Li X, Westwick J, Davis RJ, Earp HS, Wang Jr CY and Baldwin Jr AS . (2002). Mol. Cell Biol., 22, 8175–8183.

  • Ritter CA and Arteaga CL . (2003). Semin. Oncol., 30, 3–11.

  • Sah NK, Munshi A, Kurland JF, McDonnell TJ, Su B and Meyn RE . (2003). J. Biol. Chem., 278, 20593–20602.

  • Shaulian E and Karin M . (2002). Nat. Cell. Biol., 4, E131–E136.

  • Singh TR, Shankar S, Chen X, Asim M and Srivastava RK . (2003). Cancer Res., 63, 5390–5400.

  • Sobota R, Szwed M, Kasza A, Bugno M and Kordula T . (2000). Biochem. Biophys. Res. Commun., 267, 329–333.

  • Sontag E, Sontag JM and Garcia A . (1997). EMBO J., 16, 5662–5671.

  • Suzuki Y, Imai Y, Nakayama H, Takahashi K, Takio K and Takahashi R . (2001). Mol. Cell, 8, 613–621.

  • Suzuki Y, Takahashi-Niki K, Akagi T, Hashikawa T and Takahashi R . (2004). Cell Death Differ., 11, 208–216.

  • Swantek JL, Cobb MH and Geppert TD . (1997). Mol. Cell. Biol., 17, 6274–6282.

  • Tang F, Tang G, Xiang J, Dai Q, Rosner MR and Lin A . (2002). Mol. Cell. Biol., 22, 8571–8579.

  • Tang G, Minemoto Y, Dibling B, Purcell NH, Li Z, Karin M and Lin A . (2001). Nature, 414, 313–317.

  • Vanhamme L and Szpirer C . (1988). Carcinogenesis, 9, 653–655.

  • Vivo C, Liu W and Broaddus VC . (2003). J. Biol. Chem., 278, 25461–25467.

  • Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, Chin W, Jones J, Woodward A, Le T, Smith C, Smolak P, Goodwin RG, Rauch CT, Schuh JC and Lynch DH . (1999). Nat. Med., 5, 157–163.

  • Wang CY, Cusack Jr JC, Liu R and Baldwin Jr AS . (1999). Nat. Med., 5, 412–417.

  • Wen J, You KR, Lee SY, Song CH and Kim DG . (2002). J. Biol. Chem., 277, 38954–38964.

  • Zhang XD, Nguyen T, Thomas WD, Sanders JE and Hersey P . (2000). FEBS Lett., 482, 193–199.

  • Zhang XD, Zhang XY, Gray CP, Nguyen T and Hersey P . (2001). Cancer Res., 61, 7339–7348.

  • Zhou Q, Fukushima P, DeGraff W, Mitchell JB, Stetler Stevenson M, Ashkenazi A and Steeg PS . (2000). Cancer Res., 60, 2611–2615.

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Acknowledgements

We thank MP Cobb for the dominant-negative JNK vector and J Downward for Omi/HtrA2 antibody. We thank Hui Lin Chua and Colin Crean for critical reading of this manuscript. This work is supported by grants from the American Institute for Cancer Research (03A069-REN) and National Cancer Institute (R01-CA89153).

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Authors and Affiliations

  1. Department of Surgery, Indiana University School of Medicine, Indianapolis, 46202, IN, USA

    Harikrishna Nakshatri

  2. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, 46202, IN, USA

    Harikrishna Nakshatri

  3. Walther Oncology Center, Indiana University School of Medicine, Indianapolis, 46202, IN, USA

    Harikrishna Nakshatri & Poornima Bhat-Nakshatri

  4. Walther Cancer Institute, Indianapolis, 46208, IN, USA

    Harikrishna Nakshatri & Poornima Bhat-Nakshatri

  5. Department of Medicine, Indiana University School of Medicine, Indianapolis, 46202, IN, USA

    Susan E Rice

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Nakshatri, H., Rice, S. & Bhat-Nakshatri, P. Antitumor agent parthenolide reverses resistance of breast cancer cells to tumor necrosis factor-related apoptosis-inducing ligand through sustained activation of c-Jun N-terminal kinase. Oncogene 23, 7330–7344 (2004). https://doi.org/10.1038/sj.onc.1207995

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