胃腸道基質瘤屬於間質腫瘤，也是常見的胃腸道間質腫瘤。其發生率每年估計為每百萬人有10~20人，而惡性率為20~30%。70～80%的病患有原發性獲得功能的c-Kit突變，這些獲得功能的c-Kit突變會使得酪氨酸持續磷酸化，進而啟動下游與腫瘤生成相關的訊息傳遞路徑。臨床上，Imatinib mesylate（IM）為酪胺酸激酶抑制劑亦是胃腸道基質瘤的第一線藥物，然而大約50%的病患在使用IM治療兩年後會產生抗藥性。另外有15%的病患從原本有表達c-Kit轉變為沒有表達c-Kit，這些病患對於IM也出現抗藥性，因此研發針對胃腸道基質瘤以及具IM抗性的胃腸道基質瘤的化療藥物是非常重要的。熱休克蛋白90富含於大部分的組織中，功能是使其受質蛋白組合成正確結構、穩定並使之活化。超過兩百個受質蛋白與癌細胞存活及其進展是有相關的，故熱休克蛋白90可做為治療癌症的目標蛋白。在此研究中，不同的熱休克蛋白90抑制劑被使用做為探討熱休克蛋白90抑制劑促進胃腸道基質瘤細胞死亡的工具，由細胞存活試驗結果得知第四代熱休克蛋白90抑制劑AUY-922比第一代熱休克蛋白抑制劑17-AAG和第三代熱休克蛋白90抑制劑BIIB021更有效抑制胃腸道基質瘤細胞生長。在分子層面上，利用西方點墨法觀察到Akt表現減少和熱休克蛋白70增加，證實這些熱休克蛋白90抑制劑在未表達c-Kit的胃腸道基質瘤細胞AUY-922、17-AAG和BIIB021具有抑制熱休克蛋白90的功能，也觀察到這些熱休克蛋白抑制劑會造成細胞凋亡。特別的是使用磷酸蛋白陣列以及使用西方點墨法確認證實AUY-922在胃腸道基質瘤細胞62細胞株明顯抑制磷酸化肝醣合成酶激酶 3，這是之前文獻沒有發現到的。另外，發現使用siRNA抑制肝醣合成酶激酶 3α或3β會造成腸道基質瘤細胞死亡。我們的結果顯示熱休克蛋白90抑制劑並不會影響肝醣合成酶激酶 3蛋白的半衰期，但是卻會降低其訊息核糖核酸的數量。總結來說，調降肝醣合成酶激酶 3的表達在熱休克蛋白90抑制劑造成未表達c-Kit的腸道基質瘤細胞死亡中至少扮演一定的角色，也證實熱休克蛋白90抑制劑調降酶激酶 3蛋白表達是透過轉錄層面的調控，而非後轉錄層面的調控。

Gastrointestinal stromal tumor (GIST) represents the most common type of mesenchymal neoplasms of the gastrointestinal (GI) tract. The annual incidence of GIST is approximately 10-20 per million peoples. Among them, 20-30% of the GIST patients are malignant, and 70-80% of the malignant cases have gain-of-function mutations in the c-Kit gene. These c-Kit mutants are involved in activation of multiple cell survival signaling pathways and highly associated with the cellular process of tumorigenesis in GIST. In the current clinical situation, Imatinib mesylate (IM), a tyrosine kinase inhibitor (TKI), is the only approved first-line anticancer drug for GIST patients. Unfortunately, about 50% of responding patients will eventually develop drug-resistance phenotypes within 2 years during the therapy. Furthermore, approximately 15% of the c-Kit-positive GIST patients, who lost their c-Kit expression in the IM therapy, are resistant to IM. Therefore, it is important to disclose alternative chemotherapeutic drugs that can be used to treat patients with GISTs and IM-resistant GISTs. Heat shock protein-90 (HSP-90) is highly abundant in most tissues and has main functions on correcting conformation, stabilization, and activation of its client proteins. More than 200 client proteins of HSP-90 have been found so far and are involved either in cancer cell survival or in tumor malignancy. Therefore, HSP-90 may be a potential therapeutic target of cancers, and possibly for GISTs. However, the underlying molecular mechanisms of action of HSP-90 inhibitors in GISTs are unclear. In this study, three HSP-90 inhibitors were used as tools to investigate the mechanisms underlying the cell death of GIST caused by the HSP-90-inhibitors. The results showed that AUY-922, the fourth generation of HSP-90 inhibitor, was much more potent in inhibiting GIST cell growth as compared to 17-AAG and BIIB021, as revealed by the cell viability assays. At the molecular level, Western blot analysis showed that targeting HSP-90 by AUY-922, 17-AAG and BIIB021 decreased AKT expression and increased HSP-70 expression, whose results are consistent with previous studies. Induction of cell apoptosis by targeting HSP-90 with these small molecule inhibitors was also observed in this study. Interestingly, results of the phospho-protein array and Western blotting revealed that AUY-922 induced GSK-3 down-regulation in GIST-62 cells in vitro, which has not been reported previously. In addition, down-regulation of either GSK-3α or -3β by siRNA could induce GIST-62cell death. The biological effect of AUY-922 in the cells was not contributed by shortening of the half-lives of the GSK-3α and - 3β protein. Indeed, it reduced the transcriptional activity of the GSK-3 gene. In conclusion, results of the current study indicate that down-regulation GSK-3 plays at least a partial role in the AUY-922-induced GISTs cell death via attenuation of GSK-3 expression at the transcriptional level rather than through a post-transcriptional control.

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