Roles of activin and hedgehog signaling in the androgen-independent prostate cancer cells

为了探索雄激素非依赖性生长的晚期前列腺癌的治疗，研究了雄激素受体与激活素或刺激素信号之间的可能相互作用。激活素受体在前列腺癌进展中的作用前列腺癌细胞系[EF1启动子-ActRIB-IRES BGEO]被建立在雄激素非依赖性前列腺癌ALVA41(Alva-ActRIB细胞)中。ActRIB的表达不改变细胞的生长速度，但裸鼠背部移植瘤的组织学检查显示，Alva-ActRIB细胞来源的肿瘤有汗状改变。此外，ActRIB在肿瘤中的表达水平与肿瘤的恶性程度呈正相关。在接种Alva-ActRIB细胞的小鼠中，经常发现腹腔内的淋巴结转移。综上所述，通过激活素受体的信号可能在t-…中发挥重要作用。雄激素受体信号和Hedgehog信号之间的串扰Sonic Hedgehog(SHH)信号与雄激素信号相结合，对前列腺癌的形成和发育至关重要。最近，SHH信号的高激活被证明在前列腺癌的增殖、进展和转移中起着重要作用。在这份报告中，我们首次证明了GLI1，已被证明在前列腺癌的SHH信号转导中发挥核心作用，可以通过直接与雄激素受体(AR)相互作用，作为辅助抑制因子，基本上阻断AR介导的反式激活。我们的结果表明，SHH-GLI途径可能是前列腺癌从雄激素依赖状态转变为雄激素非依赖状态的决定因素之一，它通过补偿甚至取代雄激素信号来实现。因此，我们的观察表明，靶向阻断SHH-GLI途径，特别是通过阻断GLI1活性，与雄激素消融一样重要，以阻止局部肿瘤进展为晚期和转移性前列腺癌，这是目前传统疗法无法治愈的。较少

To explore the treatment of advanced prostate cancer that shows androgen-independent growth, possible interactions between androgen receptor and activin or hedgehog signaling were investigated.Role of activin receptor in the progression of prostate cancerThe prostate cancer cell lines carrying the plasmid, [EF1 promoter-ActRIB-IRES bGEO], were established in androgen independent prostate cancer cells, ALVA41 (ALVA-ActRIB cells). The cell growth rate was not changed by the expression of ActRIB, However, the histological examination of the xenograft on the back of athymic nude mice revealed that schirrous change was found in the tumor derived from ALVA-ActRIB cells. In addition, there was a positive correlation between the expression levels of ActRIB in the tumor and degree of malignancy. Lymph nodes metastases in the abdominal cavity were frequently found in the mice inoculated with the ALVA-ActRIB cells. Taken together, signaling through activin receptor may play an important role in t … More he progression of prostate cancer, thus providing the therapeutic target of advanced prostate cancer.Cross talk between Androgen receptor signaling and Hedgehog signalingSonic hedgehog (SHH) signaling, acting in a combinatorial manner with androgen signaling, is essential for prostate patterning and development. More recently, elevated activation of SHH signaling has been shown to play important roles in proliferation, progression and metastasis of prostate cancer. In this report, we demonstrate for the first time, that GLI1, which has been shown to play a central role in SHH signaling in prostate cancer, can act as a co-repressor to substantially block androgen receptor (AR)-mediated transactivation by directly interacting with AR. Our results suggest that the SHH-GLI pathway might be one of determinants governing the transition of prostate cancer from an androgen-dependent to an androgen-independent state by compensating, or even superseding androgen signaling. Therefore, our observations suggest that targeted disruption of the SHH-GLI pathway, especially by blocking GLI1 activity, is as essential as androgen ablation for counteracting progression of localized tumors to advanced and metastatic forms of prostate cancer, which are incurable by current conventional therapies. Less