摘要
背景与目的:蛋白酶体抑制剂能影响肿瘤生长并诱导细胞凋亡。PS-341作为第一个经研究证实并被美国FDA批准用于临床的蛋白酶体抑制剂,可以通过JNK通路诱导体外胶质瘤细胞凋亡。然而,PS-341在诱导细胞凋亡的同时,还将促进热休克蛋白(HSPs)的表达。HSPs有保护细胞对抗应激的作用。本研究中,我们将探索HSPs是否能保护胶质瘤细胞对抗PS-341诱导的细胞凋亡,以及抑制HSPs表达是否能够增强PS-341诱导胶质瘤细胞凋亡。方法:通过使用热休克蛋白抑制剂、亚致死热处理的方法调节胶质瘤细胞中HSPs的表达,并用流式细胞技术、台盼蓝排斥实验和Western blotting等方法检测PS-341诱导的细胞损害。结果:胶质瘤细胞经PS-341处理后,HSPs的表达上调。抑制HSPs的表达,PS-341诱导细胞凋亡的能力显著增强。结论:胶质瘤细胞中,HSPs可以保护PS-341诱导的细胞凋亡。PS-431联合应用HSPs抑制剂将增强胶质瘤细胞凋亡,这有望成为一种新的胶质瘤治疗途径。
BACKGROUND ＆ OBJECTIVE： Proteasome inhibitor have profound effects on tumor growth and cause cells to undergo apoptosis. PS-341, as an extremely potent and selective proteasome inhibitor, which is the first proteasome inhibitor to be used in clinical practice with the approve of FDA, can induces ceil death via JNK pathway in vitro in glioma. However, suppressing proteasome complex by PS-341 may induce expression of heat shock proteins （HSPs）, which confer potential protection against cellular stress. In this study, we explored whether induction of HSPs could impair PS-341-induced ceil death and whether inhibition of HSPs could enhance ceil damage induced by PS-341 in glioma ceils. METHODS： HSP expression in glioma ceils was modulated by HSP inhibitor and sublethal heat, then PS-341-induced cell damage was examined bv different methods. RESULTS： HSP level wasupregulated when glioma cells were treated with PS-341. PS-341-mediated cell damage could be significantly augmented by HSP inhibition. CONCLUSIONS： Our results demonstrated that HSPT0 impaired cell death induced by PS-341 in glioma cells. Administration of PS-341 in combination witheither HSP70 inhibitor may act as a new approach to treatment of glioma.
出处
《中国神经肿瘤杂志》
2012年第4期217-222,共6页
Chinese Journal of Neuro-Oncology
基金
国家自然科学基金项目(No 81172388 30973078)
青年科学基金项目(No 30901533)
