PERK Regulates the Sensitivity of Hepatocellular Carcinoma Cells to High-LET Carbon Ions via either Apoptosis or Ferroptosis

PERK is one of the transmembrane sensors of unfolded protein response (UPR) triggered by ER stress. In this study, we evaluated the role of PERK in the sensitivity of hepatocellular carcinoma (HCC) cells to high linear energy transfer (LET) carbon ions (CI). We found that CI irradiation could induce ER stress in HCC cells. On the one hand, PERK promoted autophagy via regulating ATF4 expression; on the other hand, PERK regulated p53 expression, and the latter either induced autophagy through up-regulating DRAM, or directly promoting apoptosis through the mitochondrial pathway or facilitating ferroptosis via down-regulating SLC7AII (the extrinsic pathway), but independent of GPX4 (the intrinsic pathway). These factors jointly determined the sensitivity of HCC cells to high-LET CI radiation. Inhibiting TPS3 directly increased cellular radioresistance definitely. Moreover, the death of HepG2 (TPS3 wild type) cells induced by high-LET CI irradiation combined with sorafenib treatment might be caused by a mixed-type regulated cell death (RCD) including both apoptosis and ferroptosis, suggesting that apoptosis and ferroptosis are synergetic cell death modes regulated by TPS3, which is one of the reasons why the sensitivity of HepG2 cells is higher than that of Hep3B (TPS3 null type) and PLC/PRF5 (TPS3 mutated type) cells. Therefore, our work might shed light on the potential therapeutic implication of CI radiotherapy combined with PERK targeted clinical drugs to implement personalized and precise treatment of HCCs.