HER2訊息途徑的活化調控雄性素受體功能與前列腺癌惡化關係之探討

Activation of HER2 Signaling Pathway Modulates AR Functions and Prostate Cancer Progression

何秉智(Ping-Chih Ho)

指導教授 ： 黃銓珍

國立臺灣大學/生命科學院/生化科學研究所/碩士(2006年)

https://doi.org/10.6342/NTU.2006.02702

摘要

前列腺癌對於雄性素去除治療法產生耐受性使其在治療上十分棘手，其中，雄性素受體持續活化可促進前列腺癌惡化及擺脫雄性素去除所造成的治療效果，正常狀態下雄性素受體受到雄性素作用調控，但是在雄性素去除治療法失效的情況下，前列腺癌細胞產生許多改變造成雄性素受體可藉由其他方式活化，在目前的研究中HER2被認為是其中一個的可能因子。HER2對於乳癌的惡化以及對tamoxifen治療產生耐受性上扮演重要的角色，然而，在前列腺癌惡化過程中HER2所扮演的角色仍然並不清楚。在此研究中，我們利用帶有PSA-reporter的22Rv1前列腺癌細胞株分析HER2促成前列腺癌惡化的訊息傳遞機制，我們發現HER2的表現量以及活化程度的提升與細胞的生長及細胞群落形成能力上升相關，此外，利用chemical genetic的方式找出PI3K、Rac1、p38以及IKKα受到
HER2 的調控，HER2 藉由PI3K-Rac1-p38-IKKα訊息途徑調控雄性素受體的活
性，另一方面，抑制這個訊息途徑將會造成前列腺癌細胞進行細胞凋亡，除此之
外，p38 的表現量與活化狀態會隨著HER2 表現量改變而同時提升，我們更近一
步的在組織免疫染色上證明HER2 表現量會隨著前列腺癌惡化而提升。綜合我們
的實驗結果，我們發現HER2 影響雄性素受體活性的訊息途徑可能是透過
PI3K-Rac1-p38-IKKα而不是藉由Akt 或Erk1/2。對於HER2 調控雄性素受體訊息
途徑的了解，將有助於提供治療目標，進而治療惡化的前列腺癌或提升治療效果。

關鍵字

雄性素 ； HER2 ； PSA ； prostate cancer

並列摘要

Escaping from androgen ablation therapy makes prostate cancer intractable. The androgen receptor (AR) remains active and supportive to the scenario of PCa development. Deregulations of normal constraints on hormone action activate AR in androgen ablation therapy. Among these deregulation mechanisms, HER2 is considered as one factor providing outlaw pathway to activate AR. HER2 is well studied in breast cancer progression and its tamoxifen resistance, but role of HER2 in prostate cancer progression remains unclear. Here we investigated the molecular basis downstream of HER2 signaling regarding prostate cancer progression. In 22Rv1 reporter cell lines, higher growth rate and colony forming ability correlate with increase of expression and activation level of HER2. We also showed that HER2-specific inhibitor AG825 decreases AR-activated transcription. Analysis on signaling molecules downstream of HER2 for involvement in AR-activated transcription revealed a complete inhibition of AR activity by targeting to PI3K, Rac1, p38α/β and IKKα IKKα. Moreover, inhibitions on these proteins decline the growth rate
and colony forming by inducing apoptosis. On the other hand, increase of p38 levels
and activities correlate with the HER2 expression level. Futhermore,
immnohistological staining in clinical tissue array demonstrated HER2 expression
levels alone with prostatic tumor progression stages. Our data suggest that HER2
overexpression promotes PCa progression might through a PI3K-Rac1-p38α/β-IKKα pathway and is independent of Akt and Erk1/2. This new pathway might
provide possible targets for treating prostate cancer or aid in prevention.

並列關鍵字

AR ； HER2 ； PSA ； 前列腺癌

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