Enzalutamide and olaparib synergistically suppress castration-resistant prostate cancer progression by promoting apoptosis through inhibiting nonhomologous end joining pathway  

作　　者：Hui-Yu Dong Pan Zang Mei-Ling Bao Tian-Ren Zhou Chen-Bo Ni Lei Ding Xu-Song Zhao Jie Li Chao Liang 

机构地区：[1]Department of Urology,The First Affiliated Hospital of Nanjing Medical University,Nanjing 210029,China [2]Department of Pathology,The First Affiliated Hospital of Nanjing Medical University,Nanjing 210029,China

出　　处：《Asian Journal of Andrology》2023年第6期687-694,共8页亚洲男性学杂志（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China(82002718);the Jiangsu Natural Science Foundation(BK20191077);Jiangsu Province Hospital(the First Affiliated Hospital of Nanjing Medical University)Clinical Capacity Enhancement Project(JSPH-MC-2021-12).

摘　　要：Recent studies revealed the relationship among homologous recombination repair(HRR),androgen receptor(AR),and poly(adenosine diphosphate-ribose)polymerase(PARP);however,the synergy between anti-androgen enzalutamide(ENZ)and PARP inhibitor olaparib(OLA)remains unclear.Here,we showed that the synergistic effect of ENZ and OLA significantly reduced proliferation and induced apoptosis in AR-positive prostate cancer cell lines.Next-generation sequencing followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed the significant effects of ENZ plus OLA on nonhomologous end joining(NHEJ)and apoptosis pathways.ENZ combined with OLA synergistically inhibited the NHEJ pathway by repressing DNA-dependent protein kinase catalytic subunit(DNA-PKcs)and X-ray repair cross complementing 4(XRCC4).Moreover,our data showed that ENZ could enhance the response of prostate cancer cells to the combination therapy by reversing the anti-apoptotic effect of OLA through the downregulation of anti-apoptotic gene insulin-like growth factor 1 receptor(IGF1R)and the upregulation of pro-apoptotic gene death-associated protein kinase 1(DAPK1).Collectively,our results suggested that ENZ combined with OLA can promote prostate cancer cell apoptosis by multiple pathways other than inducing HRR defects,providing evidence for the combined use of ENZ and OLA in prostate cancer regardless of HRR gene mutation status.

关 键 词：APOPTOSIS enzalutamide nonhomologous end joining OLAPARIB prostate cancer 

分 类 号：R737.25[医药卫生—肿瘤]