ULK2 suppresses glycolysis to attenuate cisplatin resistance in ovarian cancer organoid via c-Jun phosphorylation

Objective Resistance to platinum-based chemotherapy remains a key obstacle in ovarian cancer treatment. This study aims to investigate the role of Uncoordinated 51-like kinase 2 (ULK2) in chemoresistance of ovarian cancer and elucidate its underlying mechanisms using 3D patient-derived organoids. Methods Survival analysis was first performed using the Kaplan‒Meier plotter database. Immunohistochemical profiling delineated differential ULK2 expression patterns between chemoresistant and chemosensitive ovarian cancer tissue samples and organoids. ULK2 overexpression was achieved in cisplatin-resistant ovarian cancer organoids via lentiviral vector transduction. Then, we conducted an in-depth examination of the alterations in phosphorylated proteins induced by ULK2 overexpression using phosphoproteomics technology. To investigate the influence of ULK2 on chemosensitivity in ovarian cancer, Cell Counting Kit-8 (CCK-8) and in vivo experiments were conducted. Glycolysis was quantitatively assessed, and the underlying molecular mechanism was systematically investigated. Results ULK2 high-expression ovarian cancer exhibited enhanced chemosensitivity and conferred survival advantage. CCK-8 and mouse experiments demonstrated that ULK2 overexpression decreased cisplatin resistance in patient-derived organoids. Gene Ontology (GO) analysis of phosphoproteomics profiling highlighted the predominant role of ULK2 in metabolic processes with experimental validation demonstrating its suppression of glycolysis. Mechanistically, ULK2 attenuated c-Jun expression by phosphorylation of c-Jun at Ser243. Moreover, c-Jun overexpression counteracted the chemosensitivity and glycolytic suppression induced by the ectopic ULK2 expression in ovarian cancer. Conclusions ULK2 overcomes cisplatin resistance in ovarian cancer by downregulating glycolysis, a process mediated by phosphorylation-induced c-Jun degradation. These findings emphasized the role of ULK2 as a tumor suppressor, offering novel insights for chemotherapy in ovarian cancer.