Adenomatous polyposis coli determines sensitivity to histone deacetylase inhibitor-induced apoptosis in colon cancer cells
Adenomatous polyposis coli determines sensitivity to histone deacetylase inhibitor-induced apoptosis in colon cancer cells
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DOI：
10.1158/0008-5472.can-06-0887
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发表时间：
2006-09-15
期刊：
影响因子：
11.2
通讯作者：
Guo, Bin
中科院分区：
文献类型：
--
作者：
Huang, Xiangwei;Guo, Bin
组蛋白去乙酰化酶（HDAC）抑制剂通过未知的机制抑制恶性细胞生长并诱导细胞凋亡。在这里，我们报告说，腺瘤性息肉病大肠杆菌（APC）蛋白的表达状态决定了结肠癌细胞的相对敏感性HDAC肿瘤诱导的凋亡。HCA-7细胞（表达野生型β-连环蛋白和APC蛋白）对HDAC抑制剂丙戊酸（VPA）和辛二酰苯胺异羟肟酸诱导的细胞凋亡比SW 620或HT-29细胞（均表达突变型APC）更敏感。当野生型APC蛋白使用诱导型表达系统表达时，HT-29细胞对VPA引起的凋亡变得敏感。相反，敲低内源性APC蛋白的小干扰RNA（siRNA）阻断VPA诱导的HCA-7细胞凋亡。APC通过下调Survivin介导VPA诱导的细胞凋亡。VPA处理后，HCA-7和HT-29/APC细胞中Survivin蛋白表达降低，而SW 620和HT-29/13-Gal细胞中Survivin蛋白表达无明显变化。而敲低survivin的siRNA敏感的SW 620细胞VPA诱导的凋亡，过表达的Survivin阻断VPA诱导的HCA-7细胞凋亡。生存素转录的下调通过GSK-3 β/β-连环蛋白/Tcf-4信号分子的变化发生。VPA还诱导HCA-7细胞中蛋白酶体介导的Survivin蛋白降解。此外，我们已经表明，APC突变介导的抗凋亡可以克服与Flavopiridol，促进生存素降解的共同治疗。这些结果表明，APC是一个关键的决定因素，HDAC肿瘤诱导的结肠癌细胞凋亡和生存素是一个潜在的目标，以提高凋亡反应的HDAC抑制剂。
Inhibitors of histone deacetylases (HDAC) inhibit malignant cell growth and induce apoptosis through unknown mechanisms. Here, we report that the expression status of adenomatous polyposis coli (APC) protein determines the relative sensitivity of colon cancer cells to HDAC inhibitor-induced apoptosis. HCA-7 cells (expressing wild-type beta-catenin and APC proteins) are more sensitive to apoptosis induced by HDAC inhibitors valproic acid (VPA) and suberoylanilide hydroxamic acid than SW620 or HT-29 cells (both expressing mutant APC). When wild-type APC protein was expressed using an inducible expression system, HT-29 cells became sensitive to apoptosis in response to VPA. Conversely, knocking down of endogenous APC protein by small interfering RNA (siRNA) blocked VPA-induced apoptosis in HCA-7 cells. APC mediated VPA-induced apoptosis through down-regulation of survivin. The level of survivin protein decreased in HCA-7 and HT-29/APC cells, but not in SW620 and HT-29/13-Gal cells after VPA treatment. Whereas knocking down of survivin by siRNA sensitized SW620 cells to VPA-induced apoptosis, overexpression of survivin blocked VPA-induced apoptosis in HCA-7 cells. Down-regulation of survivin transcription occurred through changes in GSK-3 beta/beta-catenin/Tcf-4 signaling molecules. VPA also induced proteasome-mediated degradation of survivin protein in HCA-7 cells. Furthermore, we have shown that APC mutation-mediated resistance to apoptosis can be overcome by cotreatment with Flavopiridol, which promotes survivin degradation. These results suggest that APC is a critical determinant of HDAC inhibitor-induced apoptosis in colon cancer cells and survivin is a potential target to enhance apoptotic response to HDAC inhibitors.