Abstract Background: Poly ADP ribose polymerase (PARP) inhibitor resistance has emerged as a new challenge in the treatment of ovarian cancer. Intervening in cellular senescence to increase the sensitivity of ovarian cancer to olaparib has emerged as a key area of research. Objective: To determine the molecular mechanism underlying the antitumor effects of PPAR-γ agonists in promoting sensitivity to olaparib in ovarian cancer cells that induce senescence. Materials and Methods: The tumor-inhibitory effects of different PPAR-γ agonists alone or in combination with olaparib were analyzed in a subcutaneous transplanted ovarian tumor model in nude mice. β-Galactosidase (SA-β-Gal) staining and real-time PCR were used to detect changes in the cellular expression of senescence and senescence-associated secretory phenotype factors. Network pharmacological analysis revealed that the molecular mechanism underlying PPAR-γ agonist-mediated enhancement of olaparib’s anti-tumor efficacy is mechanistically linked to the SIRT1 signaling pathway. Subsequent functional validation through Western blotting and immunohistochemical analyses elucidated the critical modulatory role of SIRT1 signaling in determining olaparib sensitivity. Results: In vivo experiments showed that different PPAR-γ agonists (rosiglitazone and pioglitazone) combined with olaparib significantly reduced the volume of subcutaneously transplanted tumors in the mice. Further studies found that the PPAR-γ agonists inhibited the expression of SIRT1, attenuated olaparib-induced cellular senescence in ovarian cancer cells, and consequently inhibited tumor cell proliferation. Importantly, the SIRT1 overexpression reversed these phenotypic changes. Conclusions: PPAR-γ agonists enhance olaparib sensitivity through suppression of the SIRT1 signaling pathway and attenuation of olaparib-induced cellular senescence.
Wang et al. (Wed,) studied this question.