Targeting genotoxic and proteotoxic stress-response pathways in human prostate cancer by clinically available PARP inhibitors, vorinostat and disulfiram

0506081 - ÚMG 2020 RIV US eng J - Journal Article
Majera, D. - Skrott, Z. - Bouchal, J. - Bartkova, J. - Simkova, D. - Gachechiladze, M. - Steigerová, J. - Kurfurstova, D. - Gursky, J. - Kořínková, G. - Cwiertka, K. - Hodný, Zdeněk - Mistrik, M. - Bártek, Jiří
Targeting genotoxic and proteotoxic stress-response pathways in human prostate cancer by clinically available PARP inhibitors, vorinostat and disulfiram.
Prostate. Roč. 79, č. 4 (2019), s. 352-362. ISSN 0270-4137. E-ISSN 1097-0045
R&D Projects: GA MŠMT(CZ) LO1304; GA MZd(CZ) NV15-28628A; GA MŠMT(CZ) LM2015062
Institutional support: RVO:68378050
Keywords : disulfiram * parp * prostate cancer * proteotoxic stress * vorinostat
OECD category: Cell biology
Impact factor: 3.279, year: 2019
Method of publishing: Limited access
https://onlinelibrary.wiley.com/doi/abs/10.1002/pros.23741

Background Castration-resistant prostate cancer (PCa) represents a serious health challenge. Based on mechanistically-supported rationale we explored new therapeutic options based on clinically available drugs with anticancer effects, including inhibitors of PARP1 enzyme (PARPi), and histone deacetylases (vorinostat), respectively, and disulfiram (DSF, known as alcohol-abuse drug Antabuse) and its copper-chelating metabolite CuET that inhibit protein turnover. Methods Drugs and their combination with ionizing radiation (IR) were tested in various cytotoxicity assays in three human PCa cell lines including radio-resistant stem-cell like derived cells. Mechanistically, DNA damage repair, heat shock and unfolded protein response (UPR) pathways were assessed by immunofluorescence and immunoblotting. Results We observed enhanced sensitivity to PARPi/IR in PC3 cells consistent with lower homologous recombination (HR) repair. Vorinostat sensitized DU145 cells to PARPi/IR and decreased mutant p53. Vorinostat also impaired HR-mediated DNA repair, as determined by Rad51 foci formation and downregulation of TOPBP1 protein, and overcame radio-resistance of stem-cell like DU145-derived cells. All PCa models responded well to CuET or DSF combined with copper. We demonstrated that DSF interacts with copper in the culture media and forms adequate levels of CuET indicating that DSF/copper and CuET may be considered as comparable treatments. Both DSF/copper and CuET evoked hallmarks of UPR in PCa cells, documented by upregulation of ATF4, CHOP and phospho-eIF2 alpha, with ensuing heat shock response encompassing activation of HSF1 and HSP70. Further enhancing the cytotoxicity of CuET, combination with an inhibitor of the anti-apoptotic protein survivin (YM155, currently undergoing clinical trials) promoted the UPR-induced toxicity, yielding synergistic effects of CuET and YM155. Conclusions We propose that targeting genotoxic and proteotoxic stress responses by combinations of available drugs could inspire innovative strategies to treat castration-resistant PCa.
Permanent Link: http://hdl.handle.net/11104/0297553