Oleic acid fuels cisplatin-resistant ovarian cancer through FABP4-driven lipid uptake

作者：Ana Maria Isac, Andres Valdivia, Didi Zha, Yinu Wang, Vanessa Hernandez, Guangyuan Zhao, Chinmayee Vallabh Prabhu Dessai, Ujin Kim, Annapurna Sai Josyula, Wenan Qiang, Sandra Oršulić, Ji‐Xin Cheng, Daniela Matei · 发表于：Molecular Metabolism · 年份：2026 · DOI：10.1016/j.molmet.2026.102374 · 研究领域：Peroxisome Proliferator-Activated Receptors、Cancer, Lipids, and Metabolism、Coenzyme Q10 studies and effects

BACKGROUND: Ovarian cancer (OC) depends on lipids as fuel for metastasis and growth. We previously showed that cisplatin resistant (Pt-R) OC cells uptake higher amounts of fatty acids (FAs) compared to sensitive (Pt-S) cells, a process which facilitates cancer cell survival under cisplatin-induced oxidative stress. METHODS: Isogenic pairs of Pt-S and Pt-R OC cell lines were cultured in low serum conditions supplemented with either 50 μM oleic acid (OA, unsaturated) or 50 μM palmitic acid (PA, saturated) and used for viability assays, RNA-Sequencing, and cell cycle analysis. The effects of an OA enriched diet were assessed in intraperitoneal ovarian xenografts. The FABP inhibitor BMS-309403 was used to block lipid import in vitro and in vivo. RESULTS: Pt-R cells were less viable than Pt-S cells under serum depletion and OA rescued starvation induced inhibition of cell proliferation, with more significant effects in Pt-R compared to Pt-S cells. RNA-sequencing showed that OA promoted upregulation of cell cycle-related pathways, including G2/M checkpoints, driven by the transcription factor E2F1. Supplementation with OA increased S- and G2/M phase cell populations in both Pt-S and Pt-R cells (p < 0.05) and E2F1 inhibition reduced OA-induced cell proliferation. An OA enriched diet promoted the growth and peritoneal dissemination of Pt-R ovarian xenografts. When co-cultured with adipocytes, Pt-R cells expressed higher levels of FA transporter proteins FABP4 and CD36 compared to sen...