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Inhibitor of apoptosis proteins (IAPs) mediate collagen type XI alpha 1-driven cisplatin resistance in ovarian cancer

Oncogene volume 37, pages 4809–4820 (2018)Cite this article

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Abstract

Although, cisplatin resistance is a major challenge in the treatment of ovarian cancer, the precise mechanisms underlying cisplatin resistance are not fully understood. Collagen type XI alpha 1 (COL11A1), a gene encoding a minor fibrillar collagen of the extracellular matrix, is identified as one of the most upregulated genes in cisplatin-resistant ovarian cancer and recurrent ovarian cancer. However, the exact functions of COL11A1 in cisplatin resistance are unknown. Here we demonstrate that COL11A1 binds to integrin α1β1 and discoidin domain receptor 2 (DDR2) and activates downstream signaling pathways to inhibit cisplatin-induced apoptosis in ovarian cancer cells. Mechanistically, we show that COL11A1 activates Src-PI3K/Akt-NF-kB signaling to induce the expression of three inhibitor apoptosis proteins (IAPs), including XIAP, BIRC2, and BIRC3. Genetic and pharmacological inhibition of XIAP, BIRC2, and BIRC3 is sufficient to restore cisplatin-induced apoptosis in ovarian cancer cells in the presence of COL11A1 in ovarian cancer cells and xenograft mouse models, respectively. We also show that the components of COL11A1- integrin α1β1/DDR2- Src-PI3K/Akt-NF-kB-IAP signaling pathway serve as poor prognosis markers in ovarian cancer patients. Taken together, our results suggest novel mechanisms by which COL11A1 confers cisplatin resistance in ovarian cancer. Our study also uncovers IAPs as promising therapeutic targets to reduce cisplatin resistance in ovarian cancer, particularly in recurrent ovarian cancer expressing high levels of COL11A1.

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References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.

    Article  Google Scholar 

  2. Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, Kepp O, et al. Molecular mechanisms of cisplatin resistance. Oncogene. 2012;31:1869–83.

    Article  CAS  PubMed  Google Scholar 

  3. Xing F, Saidou J, Watabe K. Cancer associated fibroblasts (CAFs) in tumor microenvironment. Front Biosci. 2010;15:166–79.

    Article  PubMed Central  CAS  Google Scholar 

  4. Chien J, Kuang R, Landen C, Shridhar V. Platinum-sensitive recurrence in ovarian cancer: the role of tumor microenvironment. Front Oncol. 2013;3:251.

    Article  PubMed Central  PubMed  Google Scholar 

  5. Wang W, Kryczek I, Dostal L, Lin H, Tan L, Zhao L, et al. Effector T cells abrogate stroma-mediated chemoresistance in ovarian. Cancer Cell. 2016;165:1092–105.

    CAS  Google Scholar 

  6. Sethi T, Rintoul RC, Moore SM, MacKinnon AC, Salter D, Choo C, et al. Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo. Nat Med. 1999;5:662–8.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Sherman-Baust CA, Weeraratna AT, Rangel LB, Pizer ES, Cho KR, Schwartz DR, et al. Remodeling of the extracellular matrix through overexpression of collagen VI contributes to cisplatin resistance in ovarian cancer cells. Cancer Cell. 2003;3:377–86.

    Article  CAS  PubMed  Google Scholar 

  9. Armstrong T, Packham G, Murphy LB, Bateman AC, Conti JA, Fine DR, et al. Type I collagen promotes the malignant phenotype of pancreatic ductal adenocarcinoma. Clin Cancer Res. 2004;10:7427–37.

    Article  CAS  PubMed  Google Scholar 

  10. Egeblad M, Rasch MG, Weaver VM. Dynamic interplay between the collagen scaffold and tumor evolution. Curr Opin Cell Biol. 2010;22:697–706.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Cohen E, Tendler T, Lu H, Hansen CK, Kertsman J, Barrios J, et al. Collagen I provides a survival advantage to MD-1483 head and neck squamous cell carcinoma cells through phosphoinositol 3-kinase signaling. Anticancer Res. 2013;33:379–86.

    CAS  PubMed  Google Scholar 

  12. Cheon DJ, Orsulic S. Ten-gene biomarker panel: a new hope for ovarian cancer? Biomark Med. 2014;8:523–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Cheon DJ, Tong Y, Sim MS, Dering J, Berel D, Cui X, et al. A collagen-remodeling gene signature regulated by TGF-beta signaling is associated with metastasis and poor survival in serous ovarian cancer. Clin Cancer Res. 2014;20:711–23.

    Article  CAS  PubMed  Google Scholar 

  14. Wu YH, Chang TH, Huang YF, Huang HD, Chou CY. COL11A1 promotes tumor progression and predicts poor clinical outcome in ovarian cancer. Oncogene. 2014;33:3432–40.

    Article  CAS  PubMed  Google Scholar 

  15. Raglow Z, Thomas SM. Tumor matrix protein collagen XI alpha1 in cancer. Cancer Lett. 2015;357:448–53.

    Article  CAS  PubMed  Google Scholar 

  16. Wu YH, Chang TH, Huang YF, Chen CC, Chou CY. COL11A1 confers chemoresistance on ovarian cancer cells through the activation of Akt/c/EBPbeta pathway and PDK1 stabilization. Oncotarget. 2015;6:23748–63.

    PubMed Central  PubMed  Google Scholar 

  17. Jia D, Liu Z, Deng N, Tan TZ, Huang RY, Taylor-Harding B, et al. A COL11A1-correlated pan-cancer gene signature of activated fibroblasts for the prioritization of therapeutic targets. Cancer Lett. 2016;382:203–14.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Teng P-N, W G, Hood BL, Conrads KA, Hamilton CA, Maxwell GL, et al. Identification of candidate circulating cisplatin-resistant biomarkers from epithelial ovarian carcinoma cell secretomes. Br J Cancer. 2013;110:123–32.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Kleman JP, Hartmann DJ, Ramirez F, van der Rest M. The human rhabdomyosarcoma cell line A204 lays down a highly insoluble matrix composed mainly of alpha 1 type-XI and alpha 2 type-V collagen chains. Eur J Biochem. 1992;210:329–35.

    Article  CAS  PubMed  Google Scholar 

  20. Fulda S, Vucic D. Targeting IAP proteins for therapeutic intervention in cancer. Nat Rev Drug Discov. 2012;11:109–24.

    Article  CAS  PubMed  Google Scholar 

  21. Cai Q, Sun H, Peng Y, Lu J, Nikolovska-Coleska Z, McEachern D, et al. A potent and orally active antagonist (SM-406/AT-406) of multiple inhibitor of apoptosis proteins (IAPs) in clinical development for cancer treatment. J Med Chem. 2011;54:2714–26.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Li W, Li B, Giacalone NJ, Torossian A, Sun Y, Niu K, et al. BV6, an IAP antagonist, activates apoptosis and enhances radiosensitization of non-small cell lung carcinoma in vitro. J Thorac Oncol. 2011;6:1801–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Jokinen J, Dadu E, Nykvist P, Kapyla J, White DJ, Ivaska J, et al. Integrin-mediated cell adhesion to type I collagen fibrils. J Biol Chem. 2004;279:31956–63.

    Article  CAS  PubMed  Google Scholar 

  24. Vogel W, Gish GD, Alves F, Pawson T. The discoidin domain receptor tyrosine kinases are activated by collagen. Mol Cell. 1997;1:13–23.

    Article  CAS  PubMed  Google Scholar 

  25. Pramanik KC, Kudugunti SK, Fofaria NM, Moridani MY, Srivastava SK. Caffeic acid phenethyl ester suppresses melanoma tumor growth by inhibiting PI3K/AKT/XIAP pathway. Carcinogenesis. 2013;34:2061–70.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Hirai H, Sootome H, Nakatsuru Y, Miyama K, Taguchi S, Tsujioka K, et al. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther. 2010;9:1956–67.

    Article  CAS  PubMed  Google Scholar 

  27. Godwin P, Baird AM, Heavey S, Barr MP, O’Byrne KJ, Gately K. Targeting nuclear factor-kappa B to overcome resistance to chemotherapy. Front Oncol. 2013;3:120.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Wu W, Ma B, Ye H, Wang T, Wang X, Yang J, et al. Millepachine, a potential topoisomerase II inhibitor induces apoptosis via activation of NF-kappaB pathway in ovarian cancer. Oncotarget. 2016;7:52281–93.

    PubMed Central  PubMed  Google Scholar 

  29. Kunsch C, Rosen CA. NF-kappa B subunit-specific regulation of the interleukin-8 promoter. Mol Cell Biol. 1993;13:6137–46.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Ikeda K, Wang LH, Torres R, Zhao H, Olaso E, Eng FJ, et al. Discoidin domain receptor 2 interacts with Src and Shc following its activation by type I collagen. J Biol Chem. 2002;277:19206–12.

    Article  CAS  PubMed  Google Scholar 

  31. Inoue O, Suzuki-Inoue K, Dean WL, Frampton J, Watson SP. Integrin alpha2beta1 mediates outside-in regulation of platelet spreading on collagen through activation of Src kinases and PLCgamma2. J Cell Biol. 2003;160:769–80.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Pleiman CM, Hertz WM, Cambier JC. Activation of phosphatidylinositol-3’ kinase by Src-family kinase SH3 binding to the p85 subunit. Science. 1994;263:1609–12.

    Article  CAS  PubMed  Google Scholar 

  33. Hatton O, Lambert SL, Krams SM, Martinez OM. Src kinase and Syk activation initiate PI3K signaling by a chimeric latent membrane protein 1 in Epstein-Barr virus (EBV)+B cell lymphomas. PLoS ONE. 2012;7:e42610.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Konecny GE, Glas R, Dering J, Manivong K, Qi J, Finn RS, et al. Activity of the multikinase inhibitor dasatinib against ovarian cancer cells. Br J Cancer. 2009;101:1699–708.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Garcia-Pravia C, Galvan JA, Gutierrez-Corral N, Solar-Garcia L, Garcia-Perez E, Garcia-Ocana M, et al. Overexpression of COL11A1 by cancer-associated fibroblasts: clinical relevance of a stromal marker in pancreatic cancer. PLoS ONE. 2013;8:e78327.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Shen L, Yang M, Lin Q, Zhang Z, Zhu B, Miao C. COL11A1 is overexpressed in recurrent non-small cell lung cancer and promotes cell proliferation, migration, invasion and drug resistance. Oncol Rep. 2016;36:877–85.

    Article  CAS  PubMed  Google Scholar 

  37. Castells M, Milhas D, Gandy C, Thibault B, Rafii A, Delord JP, et al. Microenvironment mesenchymal cells protect ovarian cancer cell lines from apoptosis by inhibiting XIAP inactivation. Cell Death Dis. 2013;4:e887.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Gyrd-Hansen M, Meier P. IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer. Nat Rev Cancer. 2010;10:561–74.

    Article  CAS  PubMed  Google Scholar 

  39. Janzen DM, Tiourin E, Salehi JA, Paik DY, Lu J, Pellegrini M, et al. An apoptosis-enhancing drug overcomes platinum resistance in a tumour-initiating subpopulation of ovarian cancer. Nat Commun. 2015;6:7956.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Jin H, Dong YY, Zhang H, Cui Y, Xie K, Lou G. shRNA depletion of cIAP1 sensitizes human ovarian cancer cells to anticancer agent-induced apoptosis. Oncol Res. 2014;22:167–76.

    Article  PubMed  Google Scholar 

  41. Li J, Feng Q, Kim JM, Schneiderman D, Liston P, Li M, et al. Human ovarian cancer and cisplatin resistance: possible role of inhibitor of apoptosis proteins. Endocrinology. 2001;142:370–80.

    Article  CAS  PubMed  Google Scholar 

  42. Pistritto G, Trisciuoglio D, Ceci C, Garufi A, D’Orazi G. Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies. Aging. 2016;8:603–19.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Sasaki H, Sheng Y, Kotsuji F, Tsang BK. Down-regulation of X-linked inhibitor of apoptosis protein induces apoptosis in chemoresistant human ovarian cancer cells. Cancer Res. 2000;60:5659–66.

    CAS  PubMed  Google Scholar 

  44. Eckelman BP, Salvesen GS. The human anti-apoptotic proteins cIAP1 and cIAP2 bind but do not inhibit caspases. J Biol Chem. 2006;281:3254–60.

    Article  CAS  PubMed  Google Scholar 

  45. Choi YE, Butterworth M, Malladi S, Duckett CS, Cohen GM, Bratton SB. The E3 ubiquitin ligase cIAP1 binds and ubiquitinates caspase-3 and -7 via unique mechanisms at distinct steps in their processing. J Biol Chem. 2009;284:12772–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Suzuki Y, Nakabayashi Y, Takahashi R. Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death. Proc Natl Acad Sci USA. 2001;98:8662–7.

    Article  CAS  PubMed  Google Scholar 

  47. Varfolomeev E, Goncharov T, Fedorova AV, Dynek JN, Zobel K, Deshayes K, et al. c-IAP1 and c-IAP2 are critical mediators of tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB activation. J Biol Chem. 2008;283:24295–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Vucic D, Dixit VM, Wertz IE. Ubiquitylation in apoptosis: a post-translational modification at the edge of life and death. Nat Rev Mol Cell Biol. 2011;12:439–52.

    Article  CAS  PubMed  Google Scholar 

  49. Asselin E, Mills GB, Tsang BK. XIAP regulates Akt activity and caspase-3-dependent cleavage during cisplatin-induced apoptosis in human ovarian epithelial cancer cells. Cancer Res. 2001;61:1862–8.

    CAS  PubMed  Google Scholar 

  50. Xu H, Bihan D, Chang F, Huang PH, Farndale RW, Leitinger B. Discoidin domain receptors promote alpha1beta1- and alpha2beta1-integrin mediated cell adhesion to collagen by enhancing integrin activation. PLoS ONE. 2012;7:e52209.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Drs. Robert C. Bast, Michael DiPersio, and Paula McKeown-Longo for insightful discussions and critical readings of the manuscript; Dr. Nikki Cheng for CAF cells. D.-J.C. is supported by the startup fund from the Albany Medical College, the Ovarian Cancer Research Fund Ann Schreiber Mentored Investigator Award, and the AACR Gertrude B. Elion Cancer Research Award.

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Authors and Affiliations

  1. Department of Regenerative and Cancer Cell Biology, Albany Medical College, Albany, NY, 12208, USA

    Miran Rada, Sameera Nallanthighal, Jennifer Cha, Kerry Ryan, Jessica Sage, Catherine Eldred, Maria Ullo & Dong-Joo Cheon

  2. School of Science, Rensselaer Polytechnic Institute, Troy, NY, 12180, USA

    Jennifer Cha

  3. Women’s Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA

    Sandra Orsulic

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Correspondence to Dong-Joo Cheon.

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Rada, M., Nallanthighal, S., Cha, J. et al. Inhibitor of apoptosis proteins (IAPs) mediate collagen type XI alpha 1-driven cisplatin resistance in ovarian cancer. Oncogene 37, 4809–4820 (2018). https://doi.org/10.1038/s41388-018-0297-x

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