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  • Original Article
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Tissue transglutaminase expression promotes cell attachment, invasion and survival in breast cancer cells

Abstract

Distant metastasis is frequently observed in patients with breast cancer and is a major cause of cancer-related deaths in these patients. Currently, very little is known about the mechanisms that underlie the development of the metastatic phenotype in breast cancer cells. We previously found that metastatic breast cancer cells express high levels of tissue transglutaminase (TG2), but established no direct link between TG2 and metastasis. In this study, we hypothesized that TG2 plays a role in conferring the metastatic phenotype to breast cancer cells. The results obtained suggested that increased expression of TG2 in breast cancer cells contributes to their increased survival, invasion and motility. We further found that TG2 protein in a metastatic breast cancer MDA-MB231 cells was present on the cell surface in close association with integrins β1, β4 and β5. Downregulation of endogenous TG2 by small interfering RNA inhibited fibronectin (Fn)-mediated cell attachment, survival and invasion. Conversely, ectopic expression of TG2 augmented invasion of breast cancer cells and attachment to Fn-coated surfaces. We conclude that TG2 expression in breast cancer cells plays an important role in the development of the metastatic phenotype.

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References

  • Aeschlimann D, Thomazy V . (2000). Protein crosslinking in assembly and remodelling of extracellular matrices: the role of transglutaminases. Connect Tissue Res 41: 1–27.

    Article  CAS  PubMed  Google Scholar 

  • Akimov SS, Belkin AM . (2001). Cell-surface transglutaminase promotes fibronectin assembly via interaction with the gelatin-binding domain of fibronectin: a role in TGFβ-dependent matrix deposition. J Cell Sci 114: 2989–3000.

    CAS  PubMed  Google Scholar 

  • Aoudjit F, Vuori K . (2001). Integrin signaling inhibits paclitaxel-induced apoptosis in breast cancer cells. Oncogene 20: 4995–5004.

    Article  CAS  PubMed  Google Scholar 

  • Baek KJ, Kang S, Damron D, Im M . (2001). Phospholipase Cdelta1 is a guanine nucleotide exchanging factor for transglutaminase II (Galpha h) and promotes alpha 1B-adrenoreceptor-mediated GTP binding and intracellular calcium release. J Biol Chem 276: 5591–5597.

    Article  CAS  PubMed  Google Scholar 

  • Balklava Z, Verderio E, Collighan R, Gross S, Adams J, Griffin M . (2002). Analysis of tissue transglutaminase in the migration of Swiss 3T3 fibroblasts: the active-state conformation of the enzyme does not affect cell motility but it is important for its secretion. J Biol Chem 277: 16567–16575.

    Article  CAS  PubMed  Google Scholar 

  • Belkin AM, Tsurupa G, Zemskov E, Veklich Y, Weisel JW, Medved L . (2005). Transglutaminase-mediated oligomerization of the fibrin(ogen) alphaC domains promotes integrin-dependent cell adhesion and signaling. Blood 105: 3561–3568.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chandrashekar R, Tsuji N, Morales T, Ozols V, Mehta K . (1998). Cloning of a novel transglutaminase from dog heart worm with protein disulfide isomerase activity. Proc Natl Acad Sci USA 95: 531–536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen J, Kanopleva M, Multani A, Pathak S, Mehta K . (2004). Drug resistant breast cancer MCF-7 cells are paradoxically sensitive to apoptosis. J Cell Physiol 200: 223–234.

    Article  CAS  PubMed  Google Scholar 

  • Chen JS, Agarwal N, Mehta K . (2002). Multidrug-resistant MCF-7 breast carcinoma cells contain deficient intracellular calcium pools. Br Cancer Res Treat 71: 237–247.

    Article  CAS  Google Scholar 

  • Chen JS, Mehta K . (1999). Tissue transglutaminase: an enzyme with a split personality. Int J Biochem Cell Biol 31: 817–836.

    Article  CAS  PubMed  Google Scholar 

  • Cordes N, Blaese MA, Plasswilm L, Rodemann HP, Van Beuningen D . (2003). Fibronectin and laminin increase resistance to ionizing radiation and the cytotoxic drug Ukrain in human tumour and normal cells in vitro. Int J Radiat Biol 79: 709–720.

    Article  CAS  PubMed  Google Scholar 

  • Damiano JS, Cress AE, Hazlehurst LA, Shtil AA, Dalton WS . (1999). Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood 93: 1658–1667.

    CAS  PubMed  Google Scholar 

  • Damiano JS, Hazlehurst LA, Dalton WS . (2001). Cell adhesion mediated drug resistance protects K562 cells from apoptosis induced by BCR/ABL inhibition, cytotoxic drugs, and gamma-irradiation. Leukemia 15: 1232–1239.

    Article  CAS  PubMed  Google Scholar 

  • Fesus L, Piacentini M . (2002). Transglutaminase 2: an enigmatic enzyme with diverse functions. Trends Biochem Sci 27: 534–539.

    Article  CAS  PubMed  Google Scholar 

  • Han JA, Park SC . (1999). Reduction of transglutaminase-2 expression is associated with an induction of drug sensitivity in the PC-14 human lung cancer cell line. J Cancer Res Clin Oncol 125: 89–95.

    Article  CAS  PubMed  Google Scholar 

  • Hang J, Zemskov EA, Lorand L, Belkin AM . (2005). Identification of a novel recognition sequence for fibronectin within the NH2-terminal b-sandwich domain of tissue transglutaminase. J Biol Chem 280: 23675–23683.

    Article  CAS  PubMed  Google Scholar 

  • Herman JF, Mangala LS, Mehta K . (2006). Implications of increased tissue transglutaminase expression in drug-resistant breast cancer (MCF-7) cells. Oncogene 25: 3049–3058.

    Article  CAS  PubMed  Google Scholar 

  • Janiak A, Zemskov E, Belkin AM . (2006). Cell surface transglutaminase promotes RhoA activation via integrin clustering and suppression of the Src-p190RhoGAP signaling pathway. Mol Biol Cell 17: 1606–1619.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jeong JM, Murthy SN, Radek JT, Lorand L . (1995). The fibronectin-binding domain of transglutaminase. J Biol Chem 270: 5654–5658.

    Article  CAS  PubMed  Google Scholar 

  • Jiang D, Ying W, Lu Y, Wan J, Zhai Y, Liu W et al. (2003a). Identification of metastasis-associated proteins by proteomic analysis and functional exploration of interleukin-18 in metastasis. Proteomics 3: 724–737.

    Article  CAS  PubMed  Google Scholar 

  • Jiang WG, Ablin R, Douglas-Jones A, Mansel RE . (2003b). Expression of transglutaminases in human breast cancer and their possible clinical significance. Oncol Rep 10: 2039–2044.

    CAS  PubMed  Google Scholar 

  • Joshi S, Guleria R, Pan J, DiPette D, Singh US . (2006). Retinoic acid receptors and tissue tansglutaminase mediate short-term effect of retinoic acid on migration and invasion of neuroblastoma SH-SY5Y cells. Oncogene 25: 240–247.

    Article  CAS  PubMed  Google Scholar 

  • Korah R, Boots M, Wieder R . (2004). Integrin α5β1 promotes survival of growth arrested breast cancer cells: an in vitro paradigm for breast cancer dormancy in bone marrow. Cancer Res 64: 4514–4522.

    Article  CAS  PubMed  Google Scholar 

  • Leroy P, Berto F, Bourget I, Rossi B . (2004). Down-regulation of Hox A7 is required for cell adhesion and migration on fibronectin during early HL-60 monocytic differentiation. J Leukocyte Biol 75: 680–688.

    Article  CAS  PubMed  Google Scholar 

  • Lipscomb EA, Mercurio AM . (2005). Mobilization and activation of a signaling competent alpha6beta4integrin underlies its contribution to carcinoma progression. Cancer Metast Rev 24: 413–423.

    Article  CAS  Google Scholar 

  • Longtin R . (2004). Birthday of a breakthrough: fibronectin research proves important, but not as originally expected. J Natl Cancer Inst 96: 6–8.

    Article  PubMed  Google Scholar 

  • Lorand L, Graham RM . (2003). Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol 4: 140–156.

    Article  CAS  PubMed  Google Scholar 

  • Mauro L, Sisci D, Bartucci M, Salerno M, Kim J, Tam T et al. (1999). SHC-alpha5beta1 integrin interactions regulate breast cancer cell adhesion and motility. Exp Cell Res 252: 439–448.

    Article  CAS  PubMed  Google Scholar 

  • McLean GW, Carragher NO, Avizienyte E, Evans J, Brunton VG, Frame MC . (2005). The role of focal-adhesion kinase in cancer – a new therapeutic opportunity. Nat Rev Cancer 5: 505–515.

    Article  CAS  PubMed  Google Scholar 

  • Mehlen P, Puisieux A . (2006). Metastasis: a question of life or death. Nat Rev Cancer 6: 449–458.

    Article  CAS  PubMed  Google Scholar 

  • Mehta K . (2005). Mammalian transglutaminases: a family portrait. Prog Exp Tumor Res 38: 1–18.

    Article  CAS  PubMed  Google Scholar 

  • Mehta K, Fok J, Miller FR, Koul D, Sahin AA . (2004). Prognostic significance of tissue transglutaminase expression in drug-resistant and metastatic breast cancer. Clin Cancer Res 10: 8068–8076.

    Article  CAS  PubMed  Google Scholar 

  • Milakovic T, Tucholski J, McCoy E, Johnson JVW . (2004). Intracellular localization and activity state of tissue transglutaminase differentially impacts cell death. J Biol Chem 279: 8715–8722.

    Article  CAS  PubMed  Google Scholar 

  • Mishra S, Murphy LJ . (2004). Tissue transglutaminase has intrinsic kinase activity: identification of transglutaminase 2 as an insulin-like growth factor-binding protein-3 kinase. J Biol Chem 279: 23863–23868.

    Article  CAS  PubMed  Google Scholar 

  • Mishra S, Murphy LJ . (2006). The p53 oncoprotein is a substrate for tissue transglutaminase kinase activity. Biochem Biophys Res Commun 339: 726–730.

    Article  CAS  PubMed  Google Scholar 

  • Mishra S, Saleh A, Espino PS, Davie JR, Murphy LJ . (2006). Phosphorylation of histones by tissue transglutaminase. J Biol Chem 281: 5532–5538.

    Article  CAS  PubMed  Google Scholar 

  • Mohan K, Pinto D, Issekutz TB . (2003). Identification of tissue transglutaminase as a novel molecule involved in human CD8+ cell transendothelial migration. J Immunol 171: 3179–3186.

    Article  CAS  PubMed  Google Scholar 

  • Parise LV, Lee J, Juliano RL . (2000). New aspects of integrin signaling in cancer. Semin Cancer Biol 10: 407–414.

    Article  CAS  PubMed  Google Scholar 

  • Parker B, Sukumar S . (2003). Distant metastasis in breast cancer: molecular mechanisms and therapeutic targets. Cancer Biol Ther 2: 14–21.

    PubMed  Google Scholar 

  • Price LS, Leng J, Schwartz MA, Bokoch GM . (1998). Activation of Rac and Cdc42 by integrins mediates cell spreading. Mol Biol Cell 9: 1863–1871.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Priglinger SG, Alge CS, Neubauer AS, Kristen N, Hirneiss C, Eibl K et al. (2004). TGF-beta2-induced cell surface tissue transglutaminase increases adhesion and migration of RPE cells on fibronectin through the gelatin-binding domain. Invest Ophthalmol Vis Sci 45: 955–963.

    Article  PubMed  Google Scholar 

  • Singh US, Kunar MT, Kao YL, Baker KM . (2001). Role of transglutaminase II in retinoic acid-induced activation of RhoA-associated kinase. EMBO J 20: 2413–2423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sonoda Y, Matsumoto Y, Funakoshi M, Yamamoto D, Hanks SK, Kasahara T . (2000). Anti-apoptotic role of focal adhesion kinase (FAK). Induction of inhibitor-of-apoptosis proteins and apoptosis suppression by the overexpression of FAK in a human leukemic cell line, HL-60. J Biol Chem 275: 16309–16315.

    Article  CAS  PubMed  Google Scholar 

  • Verderio E, Nicholas B, Gross S, Griffin M . (1998). Regulated expression of tissue transglutaminase in Swiss 3T3 fibroblasts: effects on the processing of fibronectin, cell attachment, and cell death. Exp Cell Res 239: 119–138.

    Article  CAS  PubMed  Google Scholar 

  • Yoneda T . (2000). Cellular and molecular basis of preferential metastasis of breast cancer to bone. J Orthop Sci 5: 75–81.

    Article  CAS  PubMed  Google Scholar 

  • Zemskov EA, Janiak A, Hang J, Waghray A, Belkin AM . (2006). The role of tissue transglutaminase in cell–matrix interactions. Front Biosci 11: 1057–1076.

    Article  CAS  PubMed  Google Scholar 

  • Zhang Z, Vuori K, Reed JC, Ruoslahti E . (1995). The alpha5 beta1 integrin supports survival of cells on fibronectin and up-regulates Bcl-2 expression. Proc Natl Acad Sci USA 92: 6161–6165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported in part by grants from National Cancer Institute, CA 092115 and Cancer Support Grant, CA 16672-29. We thank Dr Ellen M McDonald for editorial help.

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Correspondence to K Mehta.

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Mangala, L., Fok, J., Zorrilla-Calancha, I. et al. Tissue transglutaminase expression promotes cell attachment, invasion and survival in breast cancer cells. Oncogene 26, 2459–2470 (2007). https://doi.org/10.1038/sj.onc.1210035

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