Identification of G-protein-coupled receptor 120 as a tumor-promoting receptor that induces angiogenesis and migration in human colorectal carcinoma

Abstract

G-protein-coupled receptor 120 (GPR120) functions as a receptor for unsaturated long-chain free fatty acids and has an important role in regulating lipid and glucose metabolism. However, a role for GPR120 in the development of tumors has not yet been clarified. Here, we show that GPR120 signaling promotes angiogenic switching and motility of human colorectal carcinoma (CRC) cells. We show that the expression of GPR120 is significantly induced in CRC tissues and cell lines, which is associated with tumor progression. Activation of GPR120 signaling in human CRC promotes angiogenesis in vitro and in vivo, largely by inducing the expression and secretion of proangiogenic mediators such as vascular endothelial growth factor (VEGF), interleukin-8 and cyclooxygenase-2-derived prostaglandin E 2 . The PI3K/Akt-NF-kB pathway is activated by GPR120 signaling and is required for GPR120 signaling-induced angiogenic switching in CRC cells. And, GPR120 activation enhances the motility of CRC cells and induces epithelial-mesenchymal transition. Furthermore, in vivo study shows that activation of GPR120 promotes angiogenesis and tumor growth. Finally, we find that GPR120 expression is positively correlated with VEGF expression and inversely correlated with the epithelial marker E-cadherin in CRC tissues. Collectively, our results demonstrate that GPR120 functions as a tumor-promoting receptor in CRC and, therefore, shows promise as a new potential target for cancer therapeutics.

Omega-3 Fatty Acids and Other FFA4 Agonists Inhibit Growth Factor Signaling in Human Prostate Cancer Cells

“…The significant p70S6K response to EPA in Caco-2 interfered with efforts to determine whether EPA exerts an inhibitory influence in these cells, i.e., the response to a combination of EPA and LPA was approximately additive (data not shown). The stimulatory effect of EPA alone in Caco-2 cells is generally consistent with the GW9508-induced activation of Akt reported previously for other colon cancer cell lines (Wu et al, 2013).…”

“…We noted that the inhibitory effects of EPA on activation of the PI3K/Akt/p70S6K pathway in prostate cancer cells, as observed in our study, contrast with the role reported for FFAR agonists in some other cancer cell models (Wu et al, 2013). In the study by Wu and coworkers (2013), the FFA1/FFA4 agonist GW9508 was shown to rapidly stimulate Akt activation when applied alone to serum-starved colon cancer cells.…”

“…In contrast to the inhibitory effects discussed earlier, a recent report indicated that FFA4 plays an oncogenic role in human colon cancer, enhancing angiogenesis as well as migration (Wu et al, 2013). With regard to signal transduction, Wu and coworkers (2013) examined direct effects of GW9508 on two colon cancer cell lines, demonstrating activation of PI3K/Akt and nuclear factor kB.…”

“…The results with colon cancer cells stand in contrast to the results reported herein for prostate cancer cells. Specifically, the FFA1/FFA4 agonist GW9508 is mitogenic for colon cancer cells (Wu et al, 2013), but not for prostate cancer cells (Fig. 7).…”

“…at ASPET Journals on April 4, 2019 jpet.aspetjournals.org cancer cell line that expresses FFA4 (Mobraten et al, 2013;Wu et al, 2013). LPA has been shown to induce proliferation of Caco-2 cells (Yun et al, 2005).…”