Lysophosphatidic acid (LPA) is a lipid mediator that mediates cellular effects via G protein-coupled receptors (GPCRs). Epidermal growth factor (EGF) is a peptide that acts via a receptor tyrosine kinase. LPA and EGF both induce proliferation of prostate cancer cells, and can transactivate each other's receptors. The LPA receptor LPA<1> is particularly important for LPA response in human prostate cancer cells. Previous work in our lab has demonstrated that FFA4, a GPCR activated by omega-3 fatty acids, inhibits responses to both LPA and EGF in these cells. One potential mechanism for the inhibition involves negative interactions between FFA4 and LPA<1>, thereby suppressing responses to EGF that require LPA<1>. In the current study, we examined the role of LPA receptors in mediating EGF and FFA4 agonist responses in two human prostate cancer cell lines, DU145 and PC-3. The results show that an LPA<1>-selective antagonist inhibits proliferation and migration to both LPA and EGF. Knockdown of LPA<1> expression, using silencing RNA, blocks responses to LPA and significantly inhibits responses to EGF. The partial response to EGF that is observed after LPA<1> knockdown is not inhibited by FFA4 agonists. Finally, the role of arrestin-3, a GPCR binding protein that mediates many actions of activated GPCRs, was tested. Knockdown of arrestin-3 completely inhibits responses to both LPA and EGF in prostate cancer cells. Taken together, these results suggest that LPA<1> plays a critical role in EGF responses, and that FFA4 agonists inhibit proliferation by suppressing positive cross-talk between LPA<1> and the EGF receptor.
The Journal of pharmacology and experimental therapeutics. 2016 Jul 29 [Epub ahead of print]
Mandi M Hopkins, Ze Liu, Kathryn E Meier
Washington State University., Washington State University., Washington State University .