Hardy et al had demonstrated the role of

Hardy et al. had demonstrated the role of GPR40 in mediating the proliferative effect of the FFA oleate's in breast cancer cells, and found that such effect can be reversed by silencing of GPR40 [14]. Similarly we have observed that inhibition of GPR40 function by its antagonist GW1100 inhibited cell proliferation in a dose dependent manner in a panel of ovarian cancer cell lines (A2780, C200, SKOV3, SKOV3ip OVCAR3, OVCAR5, PEO1 and mouse ID8 cell lines). Additionally, GW1100 was also able to inhibit cell proliferation when induced in presence of oleate. Inhibition of GPR40 has also been shown to inhibit cell motility of liver epithelial cells in presence of chemical carcinogens [20]. In endometrial cancer cell lines, the proliferative effect of oleic 873 mg was shown to be mediated via GPR120 but not GPR40 [34]. On the other hand, Nehra et al. recently reported that GPR40 stimulation was associated with a significant inhibitory effect on the growth of human melanoma in response to omega 3-fatty acids [19]. Other investigators have found that GPR40 knockdown in pancreatic cancer cells promoted motility, invasion and tumorigenicity, possibly by activation of metal matrix metallo-proteinase 2 [33]. These results suggest that the same FFA receptors may have different effects in different cancers types. A well-studied physiological role of GPR40 relates to the regulation of insulin secretion in pancreatic beta cells in response to FFAs [23]. Researchers have recently demonstrated that GPR40 signaling potentiated the glucose-stimulated insulin secretion and resulted in remodeling of lipid and energy metabolism in the pancreatic beta cells. The mechanism underlying these changes had not been reported [23]. Previously, we have shown that mouse ovarian cancer cells exposed to the adipocyte conditioned media showed higher glycolysis and oxidative phosphorylation compared to cells grown in basal media [9], indicating that ovarian cancer cells attained an increased metabolically active state. In the current research, we have observed that inhibition of GPR40 modulated the bioenergetics of the ovarian cancer cells by inhibiting oxidative phosphorylation; interestingly, there also was a concurrent increase in glycolysis. We speculate that this increase in glycolysis is likely a compensatory mechanism since it only involved the basal glycolytic rate with no associated change in the glycolytic capacity of the cells. These findings suggest that apart from serving as cellular energy sources, FFAs can also modulate the cellular energetics of the ovarian cancer cells via receptor signaling. Additionally, we have observed that combining GPR40 antagonist with a glycolytic inhibitor resulted in additive inhibition of cell proliferation. Thus, a combined approach to target the metabolic pathways in these malignant cells may be an effective therapeutic strategy. Glycolytic inhibitors such as 2 deoxyglucose (2DG) are being investigated in combination with other therapies in clinical trials targeting solid tumors [35]. A phase I trial has established a safe dose of 2DG alone or in combination with docetaxel in patients with advanced solid tumors [36]. The clinical use and safety profile of 2DG have also been described in a trial that included patients with castrate-resistant prostate cancer [37]. FFAR40 agonists have been investigated in clinical trials for diabetes and their safety in humans have been confirmed [38]. On the other hand, research on FFAR antagonists is relatively recent and laboratory data are emerging regarding its effects and potential use. The following are the supplementary data related to this article.
Conflict of interest
Funding This study was supported by Henry Ford Health System (A20017) funding and Ruth McVay (M70073) funds to RR and Patterson Endowment funds to AM.
Acknowledgements