Androgenic regulation of hedgehog signaling pathway components in prostate cancer cells.
Androgenic regulation of hedgehog signaling pathway components in prostate cancer cells.
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DOI：
10.4161/cc.8.1.7532
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发表时间：
2009-01-01
期刊：
影响因子：
4.3
通讯作者：
Buttyan, Ralph
中科院分区：
文献类型：
--
作者：
Chen, Mengqian;Tanner, Matthew;Levine, Alice C.;Levina, Elina;Ohouo, Patrice;Buttyan, Ralph
刺猬信号被认为在包括前列腺癌在内的几种人类癌症中发挥作用。尽管前列腺癌细胞表达许多参与hedgehog信号传导的基因产物，但这些细胞对外源性hedgehog配体的典型信号传导效应或对激活的Smoothened（Hedgehog调节的Gli转录激活介体）是难治的。在这里，我们表明，刺猬配体和一些刺猬靶基因的表达调节雄激素在人类前列腺癌细胞系，LNCaP及其更多的转移性变体（C4-2和C4-2B）。雄激素（R1881）强烈抑制这些细胞中hedgehog配体的表达，并且它们在雄激素缺乏培养基中的长期维持上调Sonic和Indian hedgehog mRNA和蛋白水平高达30，000倍。将刺猬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应答小鼠成纤维细胞（MC 3 T3-E1）中的刺猬靶基因表达。此外，这种活性伴随着LNCaP中Gli靶基因Patched 1和Gli 2的表达增加，这可以被环巴胺抑制，表明慢性雄激素剥夺也重新唤醒了癌细胞对hedgehog的自分泌反应。与R1881对Hedgehog配体和Gli 2表达的抑制作用相反，我们发现R1881诱导LNCaP细胞中Gli 1的表达。考虑到雄激素调节hedgehog配体的表达和释放以及这些前列腺癌细胞中自分泌hedgehog信号通路的活性的能力，我们的研究结果表明，前列腺癌的慢性雄激素剥夺治疗（ADT）可能会在肿瘤区域产生hedgehog信号环境，最终影响这种治疗的长期有效性。这一考虑支持在晚期前列腺癌患者中临床测试刺猬阻断药物与ADT联合的想法。
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.
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影响因子：
11.5
作者：
Evangelista, Marie;Tian, Hua;de Sauvage, Frederic J.
通讯作者：
de Sauvage, Frederic J.
影响因子：
2.8
作者：
Prueitt, Robyn L.;Yi, Ming;Hudson, Robert S.;Wallace, Tiffany A.;Howe, Tiffany M.;Yfantis, Harris G.;Lee, Dong. H.;Stephens, Robert M.;Liu, Chang-Gong;Calin, George A.;Croce, Carlo M.;Ambs, Stefan
通讯作者：
Ambs, Stefan
影响因子：
4.3
作者：
Lauth, Matthias;Toftgard, Rune
通讯作者：
Toftgard, Rune
DOI：
10.1016/s1078-1439(97)00039-2
发表时间：
1997-03-01
期刊：
Urologic oncology
影响因子：
--
作者：
Shen, R;Dorai, T;Buttyan, R
通讯作者：
Buttyan, R
影响因子：
37.3
作者：
Sheng, Tao;Li, Chengxin;Xie, Jingwu
通讯作者：
Xie, Jingwu