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首页> 外文期刊>Oncogene >Lysyl oxidase propeptide inhibits prostate cancer cell growth by mechanisms that target FGF-2-cell binding and signaling
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Lysyl oxidase propeptide inhibits prostate cancer cell growth by mechanisms that target FGF-2-cell binding and signaling

机译：赖氨酰氧化酶前肽通过靶向FGF-2细胞结合和信号传导的机制抑制前列腺癌细胞的生长

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Enhanced RAS signaling and decreased androgen dependence of prostate cancer cells accompany poor clinical outcomes. Elevated autocrine fibroblast growth factors 2 (FGF-2) signaling promotes prostate cancer cell growth and survival. Expression of lysyl oxidase (LOX) inhibits RAS transforming activity. LOX is secreted as 50?kDa pro-LOX protein and then undergoes extracellular proteolytic processing to form ~30?kDa LOX enzyme and ~18?kDa propeptide (LOX-PP). We have previously shown that LOX-PP inhibits breast cancer cell transformation and tumor formation, but mechanisms of action of LOX-PP have not been fully elucidated. Here we report that LOX expression is reduced in prostate cancer cell lines and that recombinant LOX-PP protein inhibits serum-stimulated DNA synthesis and MEK/ERK and PI3K/AKT pathways in DU 145 and PC-3 androgen-independent cell lines. In DU 145 cells, treatment with a pharmacologic FGF-receptor inhibitor or a neutralizing anti-FGFR1 antibody mimicked LOX-PP inhibition of serum-stimulated DNA synthesis. FGF-2-stimulated DNA synthesis, ERK1/2, AKT and FRS2α activation were found all to be inhibited by LOX-PP in DU 145 cells. LOX-PP reduced specific binding of FGF-2 to DU 145 cells, suggesting that LOX-PP targets FGF signaling at the receptor. Interestingly, PC-3 cells did not respond to FGF-2, consistent with previous reports. We conclude that LOX-PP inhibits proliferation of DU 145 cells by interfering with FGFR(s) binding and signaling, and that LOX-PP has other mechanisms of action in PC-3 cells.
机译：增强的RAS信号传导和降低的前列腺癌细胞雄激素依赖性伴随着不良的临床结果。高水平的自分泌成纤维细胞生长因子2（FGF-2）信号传导促进前列腺癌细胞的生长和存活。赖氨酰氧化酶（LOX）的表达抑制RAS转化活性。 LOX分泌为50？kDa的原LOX蛋白，然后进行细胞外蛋白水解处理，形成〜30？kDa的LOX酶和〜18？kDa的前肽（LOX-PP）。先前我们已经证明LOX-PP抑制乳腺癌细胞转化和肿瘤形成，但是尚未完全阐明LOX-PP的作用机理。在这里，我们报道在前列腺癌细胞系中LOX表达降低，并且重组LOX-PP蛋白抑制DU 145和PC-3雄激素非依赖性细胞系中血清刺激的DNA合成以及MEK / ERK和PI3K / AKT途径。在DU 145细胞中，用药理性FGF受体抑制剂或中和性抗FGFR1抗体处理可模仿LOX-PP对血清刺激的DNA合成的抑制作用。发现在DU 145细胞中，LOX-PP抑制了FGF-2刺激的DNA合成，ERK1 / 2，AKT和FRS2α的活化。 LOX-PP降低了FGF-2与DU 145细胞的特异性结合，表明LOX-PP靶向受体处的FGF信号传导。有趣的是，与以前的报道一致，PC-3细胞对FGF-2没有反应。我们得出结论，LOX-PP通过干扰FGFR（s）的结合和信号传导来抑制DU 145细胞的增殖，并且LOX-PP在PC-3细胞中具有其他作用机制。

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