Skip to main content

Advertisement

SpringerLink
Log in

Osteopontin splice variants expression is involved on docetaxel resistance in PC3 prostate cancer cells

  • Original Article
  • Published:
Tumor Biology

Abstract

Osteopontin (OPN) is a phosphoprotein that activates several aspects of tumor progression. Alternative splicing of the OPN primary transcript generates three splicing isoforms, OPNa, OPNb and OPNc. In this report, we investigated some cellular mechanisms by which OPN splice variants could mediate PC3 prostate cancer (PCa) cell survival and growth in response to docetaxel (DXT)-induced cell death. Cell survival before and after DXT treatment was analyzed by phase-contrast microscopy and crystal-violet staining assays. Quantitative real-time PCR and immunocytochemical staining assays were used to evaluate the putative involvement of epithelial-mesenchymal transition (EMT) and OPN isoforms on mediating PC3 cell survival. Upon DXT treatment, PC3 cells overexpressing OPNb or OPNc isoforms showed higher cell densities, compared to cells overexpressing OPNa and controls. Notably, cells overexpressing OPNb or OPNc isoforms showed a downregulated pattern of EMT epithelial cell markers, while mesenchymal markers were mostly upregulated in these experimental conditions. We concluded that OPNc or OPNb overexpression in PC3 cells can mediate resistance and cell survival features in response to DXT-induced cell death. Our data also provide evidence the EMT program could be one of the molecular mechanisms mediating survival in OPNb- or OPNc-overexpressing cells in response to DXT treatment. These data could further contribute to a better understanding of the mechanisms by which PCa cells acquire resistance to DXT treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Weber GF. The metastasis gene osteopontin: a candidate target for cancer therapy. Biochim Biophys Acta. 2001;1552:61–85.

    Article  CAS  PubMed  Google Scholar 

  2. Rangaswami H, Bulbule A, Kundu GC. Osteopontin: role in cell signaling and cancer progression. Trends Cell Biol. 2006;16:79–87.

    Article  CAS  PubMed  Google Scholar 

  3. Johnston NI, Gunasekharan VK, Ravindranath A, El-Tanani MK, et al. Osteopontin as a target for cancer therapy. Front Biosci. 2008;13:4361–72.

    Article  CAS  PubMed  Google Scholar 

  4. Shevde LA, Das S, Clark DW, Samant RS. Osteopontin: an effector and an effect of tumor metastasis. Curr Mol Med. 2010;10:71–81.

    Article  CAS  PubMed  Google Scholar 

  5. Ivanov S, Ivanova AV, Goparaju CM, Pass HI, et al. Tumorigenic properties of alternative osteopontin isoforms in mesothelioma. Biochem Biophys Res Commun. 2009;8:514–8.

    Article  Google Scholar 

  6. Anborgh PH, Mutrie JC, Tuck AB, Chambers AF. Pre- and post-translational regulation of osteopontin in cancer. J Cell Commun Signal. 2011;5:111–22.

    Article  PubMed  PubMed Central  Google Scholar 

  7. He B, Mirza M, Weber GF. An osteopontin splice variant induces anchorage independence in human breast cancer. Oncogene. 2006;25:2192–202.

    Article  CAS  PubMed  Google Scholar 

  8. Gimba ER, Tilli TM. Human osteopontin splicing isoforms: known roles, potential clinical applications and activated signaling pathways. Cancer Lett. 2013;331:11–7.

    Article  CAS  PubMed  Google Scholar 

  9. Blasberg J, Goparaju CM, Pass HI, Donington JS. Lung cancer osteopontin isoforms exhibit angiogenic functional heterogeneity. J Thorac Cardiovasc Surg. 2009;139:1587–93.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Mirza M, Shaughnessy E, Hurleym JK, Vanpattenm KA, Weber GF, et al. Osteopontin-c is a selective marker for breast cancer. Int J Cancer. 2008;122:889–97.

    Article  CAS  PubMed  Google Scholar 

  11. Tilli TM, Mello KD, Ferreira LB, Matos AR, Accioly MT, Gimba ER. Both osteopontin-c and osteopontin-b splicing isoforms exert pro-tumorigenic roles in prostate cancer cells. Prostate. 2012;72:1688–99.

    Article  CAS  PubMed  Google Scholar 

  12. Liang J, Slingerland JM. Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle. 2003;2:339–45.

    Article  CAS  PubMed  Google Scholar 

  13. Puhr M, Hoefer J, Schäfer G, Erb HH, Oh SJ, Culig Z, et al. Epithelial-to-mesenchymal transition leads to docetaxel resistance in prostate cancer and is mediated by reduced expression of miR-200c and miR-205. Am J Pathol. 2012;181:2188–201.

    Article  CAS  PubMed  Google Scholar 

  14. Emadi BM, Soheili ZS, Schmitz I, Sameie S, Schulz WA. Snail regulates cell survival and inhibits cellular senescence in human metastatic prostate cancer cell lines. Cell Biol Toxicol. 2010;26(6):553–67.

    Article  Google Scholar 

  15. Jennbacken K, Tesan T, Wang W, Gustavsson H, Damber JE, Welén K. N-cadherin increases after androgen deprivation and is associated with metastasis in prostate cancer. Endocr Relat Cancer. 2010;17(2):469–79.

    Article  CAS  PubMed  Google Scholar 

  16. Sánchez C, Mendoza P, Contreras HR, Vergara J, Castellón EA, et al. Expression of multidrug resistance proteins in prostate cancer is related with cell sensitivity to chemotherapeutic drugs. Prostate. 2009;69:1448–59.

    Article  PubMed  Google Scholar 

  17. Chi KN, Siu LL, Hirte H, Hotte SJ, Knox J, Eisenhauer E, et al. A phase I study of OGX-011, a 2′-methoxyethyl phosphorothioate antisense to clusterin, in combination with docetaxel in patients with advanced cancer. Clin Cancer Res. 2008;14(3):833–9.

    Article  CAS  PubMed  Google Scholar 

  18. Tolcher AW, Chi K, Kuhn J, Gleave M, Patnaik A, Rowinsky E, et al. A phase II, pharmacokinetic, and biological correlative study of oblimersen sodium and docetaxel in patients with hormone-refractory prostate cancer. Clin Cancer Res. 2002;11(10):3854–61.

    Article  Google Scholar 

  19. Patterson SG, Wei S, Chen X, Sallman DA, Gilvary DL, Djeu JY, et al. Novel role of Stat1 in the development of docetaxel resistance in prostate tumor cells. Oncogene. 2006;25(45):6113–22.

    Article  CAS  PubMed  Google Scholar 

  20. Domingo-Domenech J, Oliva C, Rovira A, Codony-Servat J, Bosch M, Mellado B, et al. Interleukin 6, a nuclear factor-kappaB target, predicts resistance to docetaxel in hormone-independent prostate cancer and nuclear factor-kappaB inhibition by PS-1145 enhances docetaxel antitumor activity. Clin Cancer Res. 2006;12(18):5578–86.

    Article  CAS  PubMed  Google Scholar 

  21. Maddika S, Ande SR, Panigrahi S, Paranjothy T, Weglarczyk K, Los M, et al. Cell survival, cell death and cell cycle pathways are interconnected: implications for cancer therapy. Drug Resist Updat. 2007;10(1–2):13–29.

    Article  CAS  PubMed  Google Scholar 

  22. Dorsey K, Agulnik M. Promising new molecular targeted therapies in head and neck cancer. Drugs. 2013;73:315–25.

    Article  CAS  PubMed  Google Scholar 

  23. Li YS, Deng ZH, Zeng C, Lei GH. Role of osteopontin in osteosarcoma. Med Oncol. 2015;32(1):49.

    CAS  Google Scholar 

  24. Nakamura T, Shinriki S, Jono H, Ueda M, Nagata M, Ando Y, et al. Osteopontin-integrin αvβ3 axis is crucial for 5-fluorouracil resistance in oral squamous cell carcinoma. FEBS Lett. 2015;589(2):231–9.

    Article  CAS  PubMed  Google Scholar 

  25. Hsu KH, Tsai HW, Lin PW, Hsu YS, Lu PJ, Shan YS. Anti-apoptotic effects of osteopontin through the up-regulation of Mcl-1 in gastrointestinal stromal tumors. World J Surg Oncol. 2014;12:189.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Graessmann M, Berg B, Fuchs B, Klein A, Graessmann A. Chemotherapy resistance of mouse WAP-SVT/t breast cancer cells is mediated by osteopontin, inhibiting apoptosis downstream of caspase-3. Oncogene. 2007;6(20):2840–50.

    Article  Google Scholar 

  27. Hsieh IS, Huang WH, Liou HC, Chuang WJ, Yang RS, Fu WM. Upregulation of drug transporter expression by osteopontin in prostate cancer cells. Mol Pharmacol. 2013;83(5):968–77.

    Article  CAS  PubMed  Google Scholar 

  28. Magadoux L, Isambert N, Plenchette S, Jeannin JF, Laurens V. Emerging targets to monitor and overcome docetaxel resistance in castration resistant prostate cancer (review). Int J Oncol. 2014;45(3):919–28.

    CAS  PubMed  Google Scholar 

  29. Sartor O, Michels RM, Massard C, de Bono JS. Novel therapeutic strategies for metastatic prostate cancer in the post-docetaxel setting. Oncologist. 2001;16(11):487–97.

    Google Scholar 

  30. Ganju A, Yallapu MM, Khan S, Behrman SW, Chauhan SC, Jaggi M. Nanoways to overcome docetaxel resistance in prostate cancer. Drug Resist Updat. 2014;17(1–2):13–23.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Chang L, Graham PH, Hao J, Ni J, Bucci J, Li Y, et al. Acquisition of epithelial-mesenchymal transition and cancer stem cell phenotypes is associated with activation of the PI3K/Akt/mTOR pathway in prostate cancer radioresistance. Cell Death Dis. 2013;24(4):e875.

    Article  Google Scholar 

  32. Arumugam T, Ramachandran V, Fournier KF, Wang H, Marquis L, Choi W, et al. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 2009;69:5820–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Leibowitz-Amit R, Joshua AM. The changing landscape in metastatic castration-resistant prostate cancer. Curr Opin Support Palliat Care. 2013;7:243–8.

    Article  PubMed  Google Scholar 

  34. Wissing MD, Van Diest PJ, Van der Wall E, Gelderblom H. Antimitotic agents for the treatment of patients with metastatic castrate-resistant prostate cancer. Expert Opin Investig Drugs. 2013;22:635–61.

    Article  CAS  PubMed  Google Scholar 

  35. Oltean S, Bates DO. Hallmarks of alternative splicing in cancer. Oncogene. 2014;33(46):311–8.

    Article  Google Scholar 

  36. Marín-Aguilera M, Codony-Servat J, Reig O, Lozano JJ, Fernández PL, Mellado B. Epithelial-to-mesenchymal transition mediates docetaxel resistance and high risk of relapse in prostate cancer. Mol Cancer Ther. 2014;13:1270–84.

    Article  PubMed  Google Scholar 

  37. Guo YL, Chakraborty S, Rajan SS, Wang R, Huang F. Effects of oxidative stress on mouse embryonic stem cell proliferation, apoptosis, senescence, and self-renewal. Stem Cells Dev. 2010;19:1321–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ewald JA, Desotelle GW, Wilding G, Jarrard DF. Therapy-induced senescence in cancer. J Natl Cancer Inst. 2010;102:1536–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Boidot R, Vegran F, Lizard-Nacol S. Predictive value of surviving alternative transcript expression in locally advanced breast cancer patients treated with neoadjuvant chemotherapy. Int J Mol Med. 2009;23:285–91.

    CAS  PubMed  Google Scholar 

  40. Thadani-Mulero M, Portella L, Sun S, Sung M, Matov A, Giannakakou P, et al. Androgen receptor splice variants determine taxane sensitivity in prostate cancer. Cancer Res. 2014;74:2270–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Couter D, Cao H, Kwok S, Kong C, Banh A, Le QT, et al. The RGD domain of human osteopontin promotes tumor growth and metastasis through activation of survival pathways. PLoS ONE. 2010;5(3):e9633.

    Article  Google Scholar 

Download references

Acknowledgments

We thank the financial support FAPERJ, CNPq, CAPES, Swiss Bridge Foundation, and INCT for Cancer Research for financial support.

Author information

Authors and Affiliations

  1. Programa de Pós Graduação em Ciências Morfológicas, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil

    K. D. M. Nakamura, A. Palumbo Jr., R. M. Mattos & L. E. Nasciutti

  2. Programa de Pós Graduação Stricto Sensu em Oncologia, Coordenação Geral Técnico Científica do Instituto Nacional de Câncer (INCa), Rio de Janeiro, RJ, Brazil

    T. M. Tilli & E. R. Gimba

  3. Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Macaé, RJ, Brazil

    J. L. Wanderley

  4. Laboratório de Hemato-Oncologia Celular e Molecular. Programa de Pesquisa em Hemato-Oncologia Molecular—CGTC, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil

    A. C. Ferreira & C. E. Klumb

  5. Departamento de Ciências da Natureza (RCN), Instituto de Humanidades e Sáude IHS, Universidade Federal Fluminense, Rua Recife s/n-Bairro Bela Vista, Rio das Ostras, Rio de Janeiro, RJ, 28895-532, Brazil

    E. R. Gimba

Authors
  1. K. D. M. Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T. M. Tilli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. L. Wanderley
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Palumbo Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R. M. Mattos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. C. Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C. E. Klumb
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. L. E. Nasciutti
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. E. R. Gimba
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. R. Gimba.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nakamura, K.D.M., Tilli, T.M., Wanderley, J.L. et al. Osteopontin splice variants expression is involved on docetaxel resistance in PC3 prostate cancer cells. Tumor Biol. 37, 2655–2663 (2016). https://doi.org/10.1007/s13277-015-4095-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-015-4095-6

Keywords

Search

Navigation