PPAR-γ agonist Inactivate Cellular Senescence by Inhibiting SIRT1 Signaling to Confer Increased Sensitivity to Olaparib in Ovarian Cancer Cells.

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: Conclusions: PPAR-γ agonists enhance olaparib sensitivity through suppression of the SIRT1 signaling pathway and attenuation of olaparib-induced cellular senescence.