Lysophosphatidic acid-regulated mitogenic ERK signaling in androgen-insensitive prostate cancer PC-3 cells
Lysophosphatidic acid-regulated mitogenic ERK signaling in androgen-insensitive prostate cancer PC-3 cells
复制标题
DOI：
10.1002/ijc.10734
复制
发表时间：
2002-12-20
影响因子：
6.4
通讯作者：
Daaka, Y
中科院分区：
文献类型：
--
作者：
Kue, PF;Taub, JS;Daaka, Y
与早期或良性标本相比，晚期和复发性前列腺肿瘤含有升高水平的活化的细胞外信号调节激酶I和2（ERK），并且抑制ERK活化减弱前列腺细胞的生长因子依赖性增殖，表明ERK在前列腺肿瘤发生中的潜在调节作用。前列腺细胞中ERK激活的因素还没有很好的定义。在这里，我们显示了雄激素不敏感的前列腺癌PC-3细胞中G蛋白偶联的溶血磷脂酸（LPA）和酪氨酸激酶表皮生长因子（EGF）受体之间的积极合作相互作用。用LPA预处理PC-3细胞降低了引发EGFR最大活化所需的EGF剂量。此外，单独用LPA处理诱导EGFR的快速（2分钟内的最大信号）酪氨酸磷酸化和随后的ERK的活化（5分钟后的最大信号），表明EGFR活化先于ERK磷酸化，并且可能构成从LPA受体到ERK的信号中继的必需组分。因此，我们表明，抑制EGFR激酶活性减弱LPA调节的ERK激活。此外，我们发现，LPA调节的EGFR酪氨酸磷酸化和ERK的激活被基质金属蛋白酶（MMP）的通用抑制剂巴马司他减弱。然而，与成纤维细胞的情况不同，我们发现LPA诱导的PC-3细胞中EGFR的反式激活不是由肝素结合EGF的脱落介导的。总之，我们的数据表明，LPA和EGF合作，以诱导前列腺癌细胞中的促有丝分裂信号在MMP调节的ERK通路的激活。(C)2002 Wiley-Liss，Inc.
Advanced and recurrent prostate tumors contain elevated levels of activated extracellular signal-regulated kinases I 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. (C) 2002 Wiley-Liss, Inc.