The Vancouver Prostate Centre and Department of Urological Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Mol Cancer Ther. 2012 Aug;11(8):1661-71. doi: 10.1158/1535-7163.MCT-12-0072. Epub 2012 Jun 6.
Hsp27 is a stress-activated multifunctional chaperone that inhibits treatment-induced apoptosis and causes treatment resistance in prostate and other cancers. We previously showed that targeted suppression of Hsp27 sensitizes cancer cells to hormone and chemotherapy. However, mechanisms by which Hsp27 confers cell treatment resistance are incompletely defined. Here, we report that Hsp27 protects human prostate cancer cells against proteotoxic stress induced by proteasome inhibition, and that Hsp27 silencing using siRNA or antisense (OGX-427) induced both apoptosis and autophagy through mechanisms involving reduced proteasome activity and induction of endoplasmic reticulum (ER) stress. We found that autophagy activation protected against ER stress-induced cell death, whereas inhibition of autophagy activation following Hsp27 silencing using either pharmacologic inhibitors or atg3 silencing enhanced cell death. Importantly, cotargeting Hsp27 and autophagy by combining OGX-427 with the autophagy inhibitor, chloroquine, significantly delayed PC-3 prostate tumor growth in vivo. These findings identify autophagy as a cytoprotective, stress-induced adaptive pathway, activated following disruption of protein homeostasis and ER stress induced by Hsp27 silencing. Combinatorial cotargeting cytoprotective Hsp27 and autophagy illustrates potential benefits of blocking activation of adaptive pathways to improve treatment outcomes in cancer.
热休克蛋白 27 是一种应激激活的多功能伴侣蛋白，可抑制治疗诱导的细胞凋亡，并导致前列腺癌和其他癌症的治疗耐药。我们之前的研究表明，靶向抑制热休克蛋白 27 可使癌细胞对激素和化疗敏感。然而，热休克蛋白 27 赋予细胞治疗耐药性的机制尚未完全确定。在这里，我们报告热休克蛋白 27 可保护人前列腺癌细胞免受蛋白酶体抑制诱导的蛋白毒性应激，并且使用 siRNA 或反义寡核苷酸（OGX-427）沉默 Hsp27 通过涉及降低蛋白酶体活性和诱导内质网（ER）应激的机制诱导细胞凋亡和自噬。我们发现自噬激活可保护细胞免受 ER 应激诱导的细胞死亡，而在用药理学抑制剂或 atg3 沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默沉默的发生的事实而表现出来的、具有普遍意义的原理或规律。真理是指客观事物及其规律在人们意识中的正确反映。
真理的客观性表现在真理的内容是不以人的意志为转移的。真理面前人人平等。
