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.
Kue
Pao F
PF
Department of Surgery (Urology), Duke University Medical Center, Durham, NC 27710, USA.
Taub
Jason S
JS
Harrington
Liza Barki
LB
Polakiewicz
Roberto D
RD
Ullrich
Axel
A
Daaka
Yehia
Y
D000728:Androgens / Q000494:pharmacology; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000502:physiology; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D020782:Matrix Metalloproteinases / Q000502:physiology; D009376:Neoplasms, Hormone-Dependent / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D000728:Androgens; D008246:Lysophospholipids; D014443:Tyrosine; D066246:ErbB Receptors; D020782:Matrix Metalloproteinases