Lysophosphatidic acid‐regulated mitogenic ERK signaling in androgen‐insensitive prostate cancer PC‐3 cells

Advanced and recurrent prostate tumors contain elevated levels of activated extracellular signal‐regulated kinases 1 and 2 (ERK) in comparison to early‐stage or benign specimens, and inhibition of ERK activation attenuates growth factor‐dependent proliferation of prostate cells, suggesting a potential regulatory role for ERK in prostate tumorigenesis. Factors responsible for ERK activation in prostate cells are not well defined. Here, we show positive cooperative interaction between the G protein‐coupled lysophosphatidic acid (LPA) and tyrosine kinase epidermal growth factor (EGF) receptors in androgen‐insensitive prostate cancer PC‐3 cells. Pre‐treatment of the PC‐3 cells with LPA decreases the dose of EGF required to elicit maximal activation of EGFR. Furthermore, treatment with LPA alone induces the rapid (maximal signal within 2 min) tyrosine phosphorylation of EGFR, and subsequent (maximal signal after 5 min) activation of ERK, suggesting that EGFR activation precedes ERK phosphorylation and may constitute a required component for signal relay from the LPA receptor to ERK. Accordingly, we show that inhibition of EGFR kinase activity attenuates the LPA‐regulated ERK activation. In addition, we find that the LPA‐regulated tyrosine phosphorylation of EGFR and activation of ERK are attenuated by batimastat, a generic inhibitor of matrix metalloproteinases (MMP). However, unlike the situation in fibroblasts, we find that the LPA‐induced transactivation of EGFR in PC‐3 cells is not mediated by shedding of heparin‐binding EGF. Together, our data show that LPA and EGF cooperate to induce mitogenic signaling in prostate cancer cells in an MMP‐regulated activation of the ERK pathway. © 2002 Wiley‐Liss, Inc.