RSL3 enhances the antitumor effect of cisplatin on prostate cancer cells via causing glycolysis dysfunction

The resistance to cisplatin (DDP) and dose-related toxicity are the two important obstacles in the chemotherapy of prostate cancer (PCa) patients. The present study demonstrated that cotreatment of DDP and RSL3, a type of small molecular compound which can inactivate glutathione peroxidase 4 (GPX4) and induce ferroptosis, synergistically inhibited the viability and proliferation of PCa cells in vitro and in vivo at low dose. In vitro studies revealed that RSL3 improved that sensitivity of PCa cells to DDP by producing ROS and aggravating the cell cycle arrest and apoptosis caused by DDP. Mechanistically, RSL3 could decrease the ATP and pyruvate content as well as the protein levels of HKII, PFKP, PKM2, which indicated that RSL3 induced glycolysis dysfunction in prostate cancer cells. Rescuing RSL3-induced glycolysis dysfunction by supplement of exterior sodium pyruvate not only inhibited RSL3/DDP-induced changes of apoptosis-related proteins levels, but also mitigated the cell death caused by RSL3/DDP. In vivo studies further confirmed that cotreatment of RSL3 and DDP at low dose significantly inhibited the growth of PCa with no obvious side effects. Taken together, we demonstrated that RSL3 improved the sensitivity of PCa to DDP via causing glycolysis dysfunction. Our findings indicated that DDP-based chemotherapy combined with RSL3 might provide a promising therapy for PCa.