Receptor interacting protein kinase 3 promotes cisplatin-induced necroptosis in apoptosis-resistant HepG2/DDP cells

Hepatocellular carcinoma is the most common primary malignancy of the liver. The chemotherapeutic drug cisplatin is widely used for advanced liver cancer. However, the development of cisplatin resistance in cancer cells, which is related to the decreased cellular susceptibility to apoptosis, results in a major limitation of cisplatin-based chemotherapy. Recently, triggering necroptosis has been proposed to be a novel therapeutic strategy to eradicate apoptosis-resistant cancer cells. In this study, we provided evidence that cisplatin could induce cell death in HepG2 cells, but not in the apoptosis-resistant HepG2/DDP cells. Ectopic expression of RIP3 promoted cisplatin-induced HepG2/DDP cells death, HMGB1 and LDH release. Moreover, we demonstrated that this type of cell death was necroptosis and depended on RIP1-RIP3-MLKL signaling pathway because inhibition of MLKL activity by necrosulfonamide (NSA) or knockdown of RIP1 significantly attenuated cisplatin-induced cell death in HepG2/DDP-RIP3 cells. Finally, we found that ectopic expression of RIP3 sensitized HepG2/DDP cancer cells to cisplatin treatment in vivo. The findings offer new insights into the molecular mechanisms underlying cisplatin-induced necroptosis in liver cancer cells and suggest that combination of cisplatin with other drugs which can restore RIP3 expression in cancer cells maybe a better choice for therapy of apoptosis-resistant cancer.