Targeting ACLY Attenuates Tumor Growth and Acquired Cisplatin Resistance in Ovarian Cancer by Inhibiting the PI3K–AKT Pathway and Activating the AMPK–ROS Pathway

Background: Ovarian cancer is the most lethal female genital malignancy. Although cisplatin first-line chemotherapy to treat ovarian patients along with debulking surgeries, its efficacy limited due high incidence of resistance. ATP citrate lyase (ACLY) has been shown be a key metabolic enzyme and associated poor prognosis in various cancers, including cancer. Nevertheless, no studies have probed mechanistic relationship between ACLY Methods: Survival analysis was mainly carried out online. Bioinformatic performed R/R studio. Proliferative activity measured by MTT colony formation assays. Cell cycle apoptosis were flow cytometry. The acquired-cisplatin-resistant cell line A2780/CDDP generated exposing A2780 at gradually elevated concentrations. assay used calculate IC 50 values cisplatin. A xenograft tumor test proliferation vivo . Results: Higher expression found tissue related prognosis. Knockdown A2780, SKOV3, HEY cells inhibited proliferation, caused cell-cycle arrest modulating P16–CDK4–CCND1 pathway, induced probably inhibiting p-AKT activity. GSE15709 dataset revealed upregulation activation PI3K–AKT pathway acquired resistance, observations on that we generated. alleviated works synergistically treatment induce activating AMPK–ROS pathway. ACLY-specific inhibitor SB-204990 showed same effect. In cells, AKT overexpression could attenuate re-sensitization knockdown. Conclusions: attenuated resistance These findings suggest combination inhibition might an effective strategy for overcoming