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首页> 外文期刊>Cell cycle >Androgenic regulation of hedgehog signaling pathway components in prostate cancer cells.
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Androgenic regulation of hedgehog signaling pathway components in prostate cancer cells.

机译：前列腺癌细胞中刺猬信号通路成分的雄激素调节。

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Hedgehog signaling is thought to play a role in several human cancers including prostate cancer. Although prostate cancer cells express many of the gene products involved in hedgehog signaling, these cells are refractory to the canonical signaling effects of exogenous hedgehog ligands or to activated Smoothened, the hedgehog-regulated mediator of Gli transcriptional activation. Here, we show that the expression of hedgehog ligands and some hedgehog target genes are regulated by androgen in the human prostate cancer cell line, LNCaP and its more metastatic variants (C4-2 and C4-2B). Androgen (R1881) strongly suppressed the expression of hedgehog ligands in these cells and their prolonged maintenance in androgen-deficient medium upregulated Sonic and Indian hedgehog mRNA and protein levels by up to 30,000-fold. Hedgehogs were released into the conditioned medium of androgen-deprived LNCaP cells and this medium was able to increase hedgehog target gene expression in hedgehog-responsive mouse fibroblasts (MC3T3-E1). Moreover, this activity was accompanied by increased expression of Gli target genes, Patched 1 and Gli2, in LNCaP that could be suppressed by cyclopamine, indicating that chronic androgen-deprivation also re-awakens the autocrine responsiveness of the cancer cells to hedgehog. In contrast to the suppressive effects of R1881 on hedgehog ligand and Gli2 expression, we found that Gli1 expression in LNCaP cells was induced by R1881. Given the ability of androgen to modulate the expression and release of hedgehog ligands and the activity of the autocrine hedgehog signaling pathway in these prostate cancer cells, our results imply that chronic androgen deprivation therapy (ADT) for prostate cancer might create a hedgehog signaling environment in the region of the tumor that could ultimately impact on the long term effectiveness of this treatment. This consideration supports the idea of clinically testing hedgehog-blocking drugs in conjunction with ADT in patients with advanced prostate cancer.
机译：刺猬信号被认为在包括前列腺癌在内的几种人类癌症中起作用。尽管前列腺癌细胞表达了许多与刺猬信号有关的基因产物，但这些细胞对于外源刺猬配体的经典信号作用或激活的，由刺猬调节的Gli转录激活介导的平滑化细胞是难治的。在这里，我们显示了在人类前列腺癌细胞系LNCaP及其更具转移性的变体（C4-2和C4-2B）中，雄激素调节刺猬配体和某些刺猬靶基因的表达。雄激素（R1881）强烈抑制了这些细胞中刺猬配体的表达，并在雄激素缺乏培养基中上调了Sonic和Indian刺猬的mRNA和蛋白质水平达30,000倍，从而延长了它们的维持时间。刺猬被释放到雄激素剥夺的LNCaP细胞的条件培养基中，并且该培养基能够增加刺猬蛋白应答小鼠成纤维细胞（MC3T3-E1）中的刺猬蛋白靶基因表达。此外，该活性伴随着LliC可能被环巴胺抑制的LNCaP中Gli靶基因Patched 1和Gli2的表达增加，这表明慢性雄激素剥夺也重新唤醒了癌细胞对刺猬的自分泌反应。与R1881对刺猬配体和Gli2表达的抑制作用相反，我们发现R1881诱导LNCaP细胞中Gli1表达。鉴于雄激素能够调节这些前列腺癌细胞中刺猬配体的表达和释放以及自分泌刺猬信号通路的活性，我们的结果表明，针对前列腺癌的慢性雄激素剥夺疗法（ADT）可能会在小鼠体内创建刺猬信号环境。可能最终影响该治疗长期效果的肿瘤区域。这种考虑支持在晚期前列腺癌患者中与ADT一起临床测试刺猬阻断药物的想法。

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