Triggering pyroptosis enhances the antitumor efficacy of PARP inhibitors in prostate cancer.

Autor: Tian A; State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai, 200030, China., Wu T; State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai, 200030, China., Zhang Y; State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai, 200030, China., Chen J; State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai, 200030, China., Sha J; Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Shandong Middle road, Shanghai, 200001, China., Xia W; State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai, 200030, China. wlxia@sjtu.edu.cn.
Jazyk: angličtina
Zdroj: Cellular oncology (Dordrecht) [Cell Oncol (Dordr)] 2023 Dec; Vol. 46 (6), pp. 1855-1870. Date of Electronic Publication: 2023 Aug 23.
DOI: 10.1007/s13402-023-00860-3
Abstrakt: Purpose: PARP inhibitors have revolutionized the treatment landscape for advanced prostate cancer (PCa) patients who harboring mutations in homologous recombination repair (HRR) genes. However, the molecular mechanisms underlying PARP inhibitors function beyond DNA damage repair pathways remain elusive, and identifying novel predictive targets that favorably respond to PARP inhibitors in PCa is an active area of research.
Methods: The expression of GSDME in PCa cell lines and human PCa samples was determined by western blotting. Targeted bisulfite sequencing, gene enrichment analysis (GSEA), clone formation, construction of the stably transfected cell lines, lactate dehydrogenase (LDH) assay, western blotting as well as a mouse model of subcutaneous xenografts were used to investigate the role of GSDME in PCa. The combinational therapeutic effect of olaparib and decitabine was determined using both in vitro and in vivo experiments.
Results: We have found low expression of GSDME in PCa. Interestingly, we demonstrated that GSDME activity is robustly induced in olaparib-treated cells undergoing pyroptosis, and that high methylation of the GSDME promoter dampens its activity in PCa cells. Intriguingly, genetically overexpressing GSDME does not inhibit tumor cell proliferation but instead confers sensitivity to olaparib. Furthermore, pharmacological treatment with the combination of olaparib and decitabine synergistically induces GSDME expression and cleavage through caspase-3 activation, thus promoting pyroptosis and enhancing anti-tumor response, ultimately resulting in tumor remission.
Conclusion: Our findings highlight a novel therapeutic strategy for enhancing the long-term response to olaparib beyond HRR-deficient tumors in PCa, underscoring the critical role of GSDME in regulating tumorigenesis.
(© 2023. Springer Nature Switzerland AG.)
Databáze: MEDLINE
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