The Activation of PI3K/AKT/mTOR Signaling Pathway in Response to Cabazitaxel Treatment in Metastatic Castration-Resistant Prostate Cancer Cells

Işıl Ezgi Eryilmaz; Gamze Güney Eskiler; Ceyda Çolakoğlu; Ünal Egeli; Gülşah Çeçener

doi:10.26650/EurJBiol.2021.1018938

Research Article

The Activation of PI3K/AKT/mTOR Signaling Pathway in Response to Cabazitaxel Treatment in Metastatic Castration-Resistant Prostate Cancer Cells

Year 2021, , 138 - 144, 17.12.2021

Işıl Ezgi Eryilmaz Gamze Güney Eskiler Ceyda Çolakoğlu Ünal Egeli Gülşah Çeçener

https://doi.org/10.26650/EurJBiol.2021.1018938

Abstract

Objective: Despite advances in treatment approaches, metastatic castration-resistant prostate cancer (mCRPC) remains a clinical challenge to treat. Cabazitaxel (Cab), a third-line chemotherapy option for mCRPC, exhibits limited efficiency due to the activation of different signaling pathways associated with drug resistance. The PI3K/AKT/mTOR activation has led to mCRPC progression, and long-term acquired Cab resistance. However, we aimed to assess the association of apoptotic efficiency of Cab with the PI3K/AKT/mTOR activation in mCRPC cells in the present study.

Materials and Methods: Cell viability, cell death, morphological analysis, PI3K/AKT/mTOR pathway activation by PI3K/MAPK dual activation assay, mRNA and miRNA expression analysis and immunofluorescence staining were performed in the Cabtreated PC3 cells.

Results: Cab caused a significant reduction in PC3 cell viability and triggered apoptotic death at 1 and 5 nM for 72 h. Cab significantly induced PI3K/AKT/mTOR activation, and increased mRNA and activated protein levels of AKT and mTOR in PC3 cells, despite its increased apoptotic effect. Furthermore, the expressions of miR-205 and miR-579, the PI3K/AKT/mTORtargeted miRNAs, were upregulated after Cab treatment. Our findings have shown that the Cab treatment activated PI3K/ AKT/mTOR pathway is associated with its apoptotic effect in mCRPC cells.

Conclusion: Although further studies are required to investigate the molecular mechanisms accompanying the Cab response in detail, the PI3K/AKT/mTOR activation, as an alteration related to the apoptotic effect of the drug, may play a role in Cab resistance in mCRPC cells, suggesting that combined therapy with PI3K/AKT/mTOR inhibitors may improve the Cab therapeutic efficiency.

Keywords

Cabazitaxel, Castration-resistant Prostate Cancer, AKT, mTOR, miRNAs

Supporting Institution

Scientific Research Projects Foundation of Bursa Uludag University

Project Number

BUAP(T)-2015/4

References

1. Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Pineros M, et al. Global cancer observatory: cancer today 2020. Lyon, France: Interna-tional Agency for Research on Cancer 2018. https://gco.iarc.fr/ today. Accessed May 27, 2021. google scholar
2. Huang Y, Jiang X, Liang X, Jiang G. Molecular and cellular mecha-nisms of castration resistant prostate cancer. Oncol Lett 2018; 15: 6063-76. google scholar
3. Lowrance WT, Roth BJ, Kirkby E, Murad MH, Cookson MS. Castra-tion-Resistant Prostate Cancer: AUA Guideline Amendment 2015. J Urol 2015; 195: 1444-52. google scholar
4. Abidi A. Cabazitaxel: A novel taxane for metastatic castration-resis-tant prostate cancer-current implications and future prospects. J Pharmacol Pharmacother 2013; 4: 230-7. google scholar
5. de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al. Prednisone plus cabazitaxel or mitoxantrone for metastat-ic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010; 376: 1147-54. google scholar
6. Nuhn P, De Bono JS, Fizazi K, Freedland SJ, Grilli M, Kantoff PW, et al. Update on Systemic Prostate Cancer Therapies: Management of Metastatic Castration-resistant Prostate Cancer in the Era of Preci-sion Oncology. Eur Urol 2019; 75: 88-99. google scholar
7. Tsao CK, Cutting E, Martin J, Oh WK. The role of cabazitaxel in the treatment of metastatic castration-resistant prostate cancer. Ther Adv Urol 2014; 6:97-104. google scholar
8. Rouyer M, Oudard S, Joly F, Fizazi K, Tubach F, Jove J, et al. Overall and progression-free survival with cabazitaxel in metastatic castra-tion-resistant prostate cancer in routine clinical practice: the FUJI cohort. Br J Cancer 2019; 121: 1001-8. google scholar
9. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 2010; 18: 11-22. google scholar
10. Bitting RL, Armstrong AJ. Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer. Endocr Relat Cancer 2013; 20: R83-99. google scholar
11. Martini M, De Santis MC, Braccini L, Gulluni F, Hirsch E. PI3K/AKT signaling pathway and cancer: an updated review. Ann Med 2014; 46: 372-83. google scholar
12. Liu Z, Zhu G, Getzenberg RH, Veltri RW. The Upregulation of PI3K/ Akt and MAP Kinase Pathways is Associated with Resistance of Mi-crotubule-Targeting Drugs in Prostate Cancer. J Cell Biochem 2015; 116: 1341-9. google scholar
13. Paller CJ, Antonarakis ES. Cabazitaxel: a novel second-line treat-ment for metastatic castration-resistant prostate cancer. Drug Des Devel Ther 2011; 5: 117-24. google scholar
14. Hongo H, Kosaka T, Oya M. Analysis of cabazitaxel-resistant mech-anism in human castration-resistant prostate cancer. Cancer Sci 2018; 109: 2937-45. google scholar
15. Bumbaca B, Li W. Taxane resistance in castration-resistant prostate cancer: mechanisms and therapeutic strategies. Acta Pharm Sin B 2018; 8: 518-29. google scholar
16. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502-12. google scholar
17. Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxan-trone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351: 1513-20. google scholar
18. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2002; 2: 48-58. google scholar
19. Duran GE, Derdau V, Weitz D. Cabazitaxel is more active than first-generation taxanes in ABCB1(+) cell lines due to its reduced affinity for P-glycoprotein. Cancer Chemother Pharmacol 2018; 81: 1095-103. google scholar
20. de Wit R, de Bono J, Sternberg CN, Fizazi K, Tombal B, Wülfing C, et al. Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer. N Engl J Med 2019; 381: 2506-18. google scholar
21. Janku F, Yap TA, Meric-Bernstam F. Targeting the PI3K pathway in cancer: are we making headway? Nat Rev Clin Oncol 2018; 15: 27391. google scholar
22. Malik SN, Brattain M, Ghosh PM, Troyer DA, Prihoda T, Bedolla R, et al. Immunohistochemical demonstration of phospho-Akt in high Gleason grade prostate cancer. Clin Cancer Res 2002; 8: 1168-71. google scholar
23. Kosaka T, Miyajima A, Shirotake S, Suzuki E, Kikuchi E, Oya M. Long-term androgen ablation and docetaxel up-regulate phosphory-lated Akt in castration resistant prostate cancer. J Urol 2011; 185: 2376-81. google scholar
24. Mulholland DJ, Tran LM, Li Y, Cai H, Morim A, Wang S. et al. Cell au-tonomous role of PTEN in regulating castration-resistant prostate cancer growth. Cancer Cell 2011; 19: 792-804. google scholar
25. Bhatnagar N, Li X, Padi SKR, Zhang Q, Thang M-S, Guo B. Downreg-ulation of miR-205 and miR-31 confers resistance to chemothera-py-induced apoptosis in prostate cancer cells. Cell Death Dis 2010; 1: e105. google scholar
26. Hagman Z, Haflidadottir BS, Ceder JA, Larne O, Bjartell A, Lilja H, et al. miR-205 negatively regulates the androgen receptor and is associated with adverse outcome of prostate cancer patients. Br J Cancer 2003; 108: 1668-76. google scholar
27. Pashaei E, Pashaei E, Ahmady M, Ozen M, Aydin N. Meta-analysis of miRNA expression profiles for prostate cancer recurrence follow-ing radical prostatectomy. PLoS One 2017; 12: e0179543. google scholar
28. Kalhori MR, Irani S, Soleimani M, Arefian E, Kouhkan F. The effect of miR-579 on the PI3K/AKT pathway in human glioblastoma PTEN mutant cell lines. J Cell Biochem 2019; 120: 16760-74. google scholar
29. Zhang X, Shu L, Hosoi H, Murti KG, Houghton PJ. Predominant nu-clear localization of mammalian target of rapamycin in normal and malignant cells in culture. J Biol Chem 2002; 277: 28127-34. google scholar
30. Tsang CK, Liu H, Zheng XF. mTOR binds to the promoters of RNA polymerase I- and III-transcribed genes. Cell Cycle 2010; 953-7. google scholar
31. Warner JR, Vilardell J, Sohn JH. Economics of ribosome biosynthe-sis. Cold Spring Harb Symp Quant Biol 2001; 66: 567-74. google scholar