A mechanism of PDAC radioresistance: Crosstalk between radiation-induced autophagy and G2 checkpoint activation

Autophagy and cell-cycle checkpoints act in concert to confer cellular radioresistance. We investigated the functional interaction between radiation-induced autophagy and G2 checkpoint activation in highly radioresistant human pancreatic ductal adenocarcinoma (PDAC) cells. Four human PDAC cell lines (MIA PaCa-2, KP-4, Panc-1 and SUIT-2) were analyzed. Autophagy and G2/M accumulation were synchronously induced in human PDAC cells with an activated G2 checkpoint at 12 h after X-ray irradiation of 6 Gy. Radiation-induced autophagy produced the ATP levels required for cell survival. G2 checkpoint inhibitors exposure attenuated not only G2 checkpoint activation but also post-irradiation autophagy, indicating the dependence of radiation-induced autophagy on an activated G2 checkpoint. MK-1775 significantly suppressed the tumor growth of MIA PaCa-2 xenografts in combination with X-rays compared to other treatment groups to enhance the radiosensitivity of PDAC cells in vivo. A biological crosstalk exists between the G2 checkpoint activation and radiation-induced autophagy processes that are believed to independently contribute to the radioresistance of human PDAC cells.第80回日本癌学会学会総