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方法，研究了雄激素受体与激活素或刺猬信号传导之间可能的相互作用。激活素受体在前列腺癌进展中的作用携带质粒[EF1启动子- actrib - ires bGEO]的前列腺癌细胞系在雄激素非依赖性前列腺癌细胞ALVA41 （ALVA-ActRIB细胞）中建立。ActRIB的表达没有改变细胞的生长速度，但对胸腺裸鼠背部的异种移植物进行组织学检查发现，由ALVA-ActRIB细胞衍生的肿瘤发生了棘状瘤变。此外，ActRIB在肿瘤中的表达水平与恶性程度呈正相关。在接种了ALVA-ActRIB细胞的小鼠腹腔中经常发现淋巴结转移。综上所述，激活素受体的信号通路可能在前列腺癌的进展过程中发挥重要作用，从而为晚期前列腺癌的治疗提供了靶点。雄激素受体信号和Hedgehog基因信号之间的串扰Hedgehog基因（SHH）信号与雄激素信号联合作用，对前列腺的形成和发育至关重要。最近，SHH信号的激活升高在前列腺癌的增殖、进展和转移中发挥了重要作用。在本报告中，我们首次证明，GLI1在前列腺癌的SHH信号传导中发挥核心作用，可以作为一种共同抑制因子，通过直接与AR相互作用，实质性地阻断雄激素受体（AR）介导的转激活。我们的研究结果表明，sh - gli途径可能是控制前列腺癌从雄激素依赖状态向雄激素独立状态转变的决定因素之一。甚至取代雄激素信号。因此，我们的观察结果表明，靶向破坏sh - gli通路，特别是通过阻断GLI1活性，与雄激素消融一样重要，可以抑制局部肿瘤向晚期和转移性前列腺癌的进展，这是目前常规疗法无法治愈的。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