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

激活素和刺猬信号在雄激素非依赖性前列腺癌细胞中的作用

基本信息

批准号：
18591029
负责人：
NOMURA Masatoshi
金额：
$ 2.39万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

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

为了探索显示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]在雄激素非依赖性前列腺癌细胞 ALVA41（ALVA-ActRIB 细胞）中建立。细胞生长速率不因的表达而改变。然而，ActRIB对无胸腺裸鼠背部异种移植物的组织学检查显示，ALVA-ActRIB细胞来源的肿瘤中发现了水样变化，并且肿瘤中ActRIB的表达水平呈正相关。接种 ALVA-ActRIB 细胞的小鼠中经常发现腹腔淋巴结转移。总而言之，通过激活素受体的信号传导可能发挥了作用。在前列腺癌的进展中发挥着重要作用，从而为晚期前列腺癌提供了治疗靶点。雄激素受体信号传导与 Hedgehog 信号传导之间的串扰音刺猬 (SHH) 信号传导与雄激素信号传导以组合方式发挥作用，对于前列腺至关重要最近，SHH 信号传导的升高已被证明在前列腺癌的增殖、进展和转移中发挥重要作用，在本报告中，我们首次证明了 GLI1，它已被证明在前列腺癌的 SHH 信号传导中发挥核心作用，可以作为辅助阻遏物，通过与 AR 直接相互作用来显着阻断雄激素受体 (AR) 介导的反式激活。通过补偿甚至取代雄激素信号传导，控制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。因此，我们的观察表明，有针对性地破坏 SHH-GLI 通路，尤其是通过阻断 GLI1 活性，与雄激素消融一样，对于阻止局部肿瘤进展为晚期和转移性前列腺癌至关重要，而目前的传统疗法无法治愈这种疾病。