FABP4 Mediated Fatty Acid Transport Promotes Proliferation and Survival of Platinum-Resistant Ovarian Cancer Cells

Background: Ovarian cancer (OC) depends on fat as fuel for metastasis and growth. We previously demonstrated 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. Results: Here we report that Pt-R OC cells are dependent on unsaturated FAs compared to Pt-S cells and upregulate key lipid transporters to allow increased uptake of FAs. Cell viability assays showed Pt-R cells were less viable under serum depletion, with oleic acid (OA, unsaturated) promoting proliferation of OC cells. OA alone rescued the inhibition of cell proliferation under conditions of serum depletion exerting more significant effects in Pt-R vs Pt-S cells. OA also reduced apoptosis, as shown by Annexin V assays, and decreased Caspase-3 and -8 cleavage. RNA-sequencing analysis linked OA-rescued cell proliferation to upregulation of cell cycle-related pathways, including G2/M checkpoints, driven by E2F1. OA increased S- and G2/M phase cell populations (6.95% to 11.6%; p<0.05), while E2F1 inhibition reduced OA-induced cell proliferation. Pt-R cells also expressed higher levels of FA transporter proteins FABP4 and CD36. Inhibiting FABPs reduced the IC50 to Pt and blocked OC growth in vivo. FABP4 was overexpressed in metastatic and recurrent vs. primary ovarian tumors. Implication: Pt-R OC cells are dependent on unsaturated FAs compared to Pt-S cells and upregulate key transporters to increase FAs uptake. OA supports proliferation of Pt-R cells by promoting cell cycle progression from G1 to S- and G2/M phases. Inhibiting FA transport reduces OC progression in vivo.