The Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
Mol Cancer Res. 2011 Dec;9(12):1755-66. doi: 10.1158/1541-7786.MCR-11-0379. Epub 2011 Oct 10.
Clusterin is a stress-activated, cytoprotective chaperone that confers broad-spectrum treatment resistance in cancer. However, the molecular mechanisms mediating CLU transcription following anticancer treatment stress remain incompletely defined. We report that Y-box binding protein-1 (YB-1) directly binds to CLU promoter regions to transcriptionally regulate clusterin expression. In response to endoplasmic reticulum stress inducers, including paclitaxel, YB-1 is translocated to the nucleus to transactivate clusterin. Furthermore, higher levels of activated YB-1 and clusterin are seen in taxane-resistant, compared with parental, prostate cancer cells. Knockdown of either YB-1 or clusterin sensitized prostate cancer cells to paclitaxel, whereas their overexpression increased resistance to taxane. Clusterin overexpression rescued cells from increased paclitaxel-induced apoptosis following YB-1 knockdown; in contrast, however, YB-1 overexpression did not rescue cells from increased paclitaxel-induced apoptosis following clusterin knockdown. Collectively, these data indicate that YB-1 transactivation of clusterin in response to stress is a critical mediator of paclitaxel resistance in prostate cancer.
簇集蛋白是一种应激激活的、细胞保护性分子伴侣，它赋予癌症广泛的治疗耐药性。然而，介导抗癌治疗应激后 CLU 转录的分子机制仍不完全明确。我们报告 Y 盒结合蛋白 1（YB-1）可直接与 CLU 启动子区域结合，从而转录调节簇集蛋白的表达。在内质网应激诱导物（包括紫杉醇）的作用下，YB-1 易位到细胞核中转激活簇集蛋白。此外，与亲本前列腺癌细胞相比，在紫杉烷耐药性前列腺癌细胞中观察到更高水平的活化 YB-1 和簇集蛋白。YB-1 或簇集蛋白的敲低使前列腺癌细胞对紫杉醇敏感，而它们的过表达则增加了对紫杉烷的耐药性。簇集蛋白的过表达可挽救 YB-1 敲低后紫杉醇诱导的细胞凋亡增加，而相反，簇集蛋白的过表达不能挽救 YB-1 敲低后紫杉醇诱导的细胞凋亡增加。总之，这些数据表明，YB-1 对簇集蛋白的应激转录激活是前列腺癌中紫杉醇耐药性的关键介导物。
