Oleic acid stimulates proliferation of RMG-1 ovarian cancer cells by activating the pentose phosphate pathway and glutamine metabolism.

Extracellular fatty acids (FAs) play an important role in regulating cellular functions such as cell proliferation, survival, and migration. The effects of oleic acid (OA) on cancer cells vary depending on the cell type. Our prior study showed that two distinct ovarian cancer cell lines, RMG-1 and HNOA, proliferate in response to OA, but they differ with respect to glucose utilization. Here, we aimed to elucidate the mechanism(s) by which OA stimulates proliferation of RMG-1 cells. We found that OA stimulates RMG-1 proliferation by activating the FA transporter CD36. OA also increases uptake of glucose and glutamine, which subsequently activate the pentose phosphate pathway (PPP) and glutamine metabolism, respectively. Given that ribose 5-phosphate derived from the PPP is utilized for glutamine metabolism and the subsequent de novo nucleotide synthesis, our findings suggest that OA affects the PPP associated with Gln metabolism, rather than glycolysis associated with glutaminolysis; this leads ultimately to activation of DNA synthesis, which is required for cell proliferation. This selective activation by OA contrasts with the mechanisms observed in HNOA cells, in which OA-induced cell proliferation is driven by transcriptional regulation of the GLUT gene. The diverse responses of cancer cells to OA may be attributed to distinct mechanisms of OA reception and/or different metabolic pathways activated by OA.