Abstract
Most pancreatic cancer patients exhibit inherent resistance to radiation therapy, and the molecular mechanisms remain poorly understood. Here, we demonstrate that phosphoglycerate kinase 1 (PGK1), a key ATP-producing glycolytic enzyme, plays a critical role in pancreatic ductal adenocarcinoma (PDAC) radioresistance. In response to ionizing radiation (IR), casein kinase 2 (CK2) is activated and phosphorylates PGK1 at S256. Phosphorylated PGK1 interacts with microrchidia CW-type zinc finger 2 (MORC2). Importantly, PGK1 functions as a protein kinase and phosphorylates MORC2 at S711, thereby enhancing the DNA-dependent ATPase activity of MORC2 to facilitate chromatin remodeling and DNA repair. Disruption of CK2-mediated PGK1 phosphorylation or PGK1-dependent MORC2 phosphorylation sensitizes PDAC cells and mouse tumors to IR. Clinically, the levels of PGK1 pS256 and MORC2 pS711, which are mutually correlated, are positively associated with poor survival in radiotherapy-treated PDAC specimens. These findings highlight the critical role of the nonmetabolic functions of PGK1 in DNA damage repair and PDAC radioresistance.