Hedgehog/Gli supports androgen signaling in androgen deprived and androgen independent prostate cancer cells.
Hedgehog/Gli supports androgen signaling in androgen deprived and androgen independent prostate cancer cells.
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DOI：
10.1186/1476-4598-9-89
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发表时间：
2010-04-26
期刊：
影响因子：
37.3
通讯作者：
Buttyan R
中科院分区：
文献类型：
--
作者：
Chen M;Feuerstein MA;Levina E;Baghel PS;Carkner RD;Tanner MJ;Shtutman M;Vacherot F;Terry S;de la Taille A;Buttyan R
抗去势前列腺癌(CRPC)是晚期前列腺癌患者应用激素疗法消耗雄激素的结果。CRPC细胞能够在低雄激素环境中生长，这与其内源性雄激素受体(AR)的异常活动有关，尽管患者全身雄激素水平较低。因此，重新激活的肿瘤细胞雄激素信号通路被认为是控制CRPC的靶点。在此之前，我们曾报道过雄激素缺乏对雄激素敏感的前列腺癌细胞Hedgehog(HH)信号被有条件地激活，在此，我们研究了雄激素缺乏和雄激素非依赖性(AI)前列腺癌细胞中HH和雄激素信号活性之间的相互作用的可能性。用HH抑制剂环多巴胺治疗各种雄激素缺乏或AI前列腺癌细胞，导致雄激素调节基因表达的剂量依赖性调节。环多巴胺对雄激素缺乏和AI前列腺癌细胞内源性雄激素调节基因表达的影响与环多巴胺对两种不同雄激素依赖启动子报告基因(荧光素酶)表达的抑制作用一致。同样，降低Smo和siRNA的表达共同抑制雄激素诱导的雄激素诱导的KLK2和KLK3的表达，而不影响雄激素受体(AR)的表达。环多巴胺还可以阻止AI细胞从雄激素依赖的亲代LNCaP细胞中生长出来，并抑制一个明显的AI-LNCaP变体的生长，而补充雄激素(R1881)则在环多巴胺存在的情况下恢复AI细胞的生长。相反，在没有雄激素的情况下，在LNCaP细胞中过表达Gli1或Gli2会增强AR特异性基因的表达。过表达的Gli1/Gli2也使亲本LNCaP细胞在雄激素耗竭的培养液中生长。293T细胞裂解液中的AR蛋白与Gli2蛋白共沉淀。总之，我们的结果表明，在低雄激素环境中，HH/Gli信号支持雄激素信号和前列腺癌细胞的AI生长。Gli2与AR蛋白共沉淀的发现表明，在这种情况下，这些蛋白之间的相互作用可能是Hedgehog/Gli支持雄激素信号转导的基础。
Castration resistant prostate cancer (CRPC) develops as a consequence of hormone therapies used to deplete androgens in advanced prostate cancer patients. CRPC cells are able to grow in a low androgen environment and this is associated with anomalous activity of their endogenous androgen receptor (AR) despite the low systemic androgen levels in the patients. Therefore, the reactivated tumor cell androgen signaling pathway is thought to provide a target for control of CRPC. Previously, we reported that Hedgehog (Hh) signaling was conditionally activated by androgen deprivation in androgen sensitive prostate cancer cells and here we studied the potential for cross-talk between Hh and androgen signaling activities in androgen deprived and androgen independent (AI) prostate cancer cells. Treatment of a variety of androgen-deprived or AI prostate cancer cells with the Hh inhibitor, cyclopamine, resulted in dose-dependent modulation of the expression of genes that are regulated by androgen. The effect of cyclopamine on endogenous androgen-regulated gene expression in androgen deprived and AI prostate cancer cells was consistent with the suppressive effects of cyclopamine on the expression of a reporter gene (luciferase) from two different androgen-dependent promoters. Similarly, reduction of smoothened (Smo) expression with siRNA co-suppressed expression of androgen-inducible KLK2 and KLK3 in androgen deprived cells without affecting the expression of androgen receptor (AR) mRNA or protein. Cyclopamine also prevented the outgrowth of AI cells from androgen growth-dependent parental LNCaP cells and suppressed the growth of an overt AI-LNCaP variant whereas supplemental androgen (R1881) restored growth to the AI cells in the presence of cyclopamine. Conversely, overexpression of Gli1 or Gli2 in LNCaP cells enhanced AR-specific gene expression in the absence of androgen. Overexpressed Gli1/Gli2 also enabled parental LNCaP cells to grow in androgen depleted medium. AR protein co-immunoprecipitates with Gli2 protein from transfected 293T cell lysates. Collectively, our results indicate that Hh/Gli signaling supports androgen signaling and AI growth in prostate cancer cells in a low androgen environment. The finding that Gli2 co-immunoprecipitates with AR protein suggests that an interaction between these proteins might be the basis for Hedgehog/Gli support of androgen signaling under this condition.
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影响因子：
4.3
作者：
Chen, Mengqian;Tanner, Matthew;Levine, Alice C.;Levina, Elina;Ohouo, Patrice;Buttyan, Ralph
通讯作者：
Buttyan, Ralph
影响因子：
64.8
作者：
KINZLER, KW;RUPPERT, JM;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
11.8
作者：
Jiang J;Hui CC
通讯作者：
Hui CC
DOI：
10.1038/nrc2503
发表时间：
2008-10
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.3
作者：
Lauth, Matthias;Toftgard, Rune
通讯作者：
Toftgard, Rune