生物
胃蛋白酶抑制剂
组织蛋白酶L
细胞凋亡
安提潘
组织蛋白酶B
程序性细胞死亡
自噬
组织蛋白酶D
细胞毒性
组织蛋白酶
分子生物学
白藜芦醇
癌症研究
细胞生物学
亮佩平
蛋白酶
生物化学
酶
体外
作者
Keng Fu Hsu,Chao Wu,Shih-Chang Huang,Ching Ming Wu,Jenn Ren Hsiao,Yi Te Yo,Yu-Hung Chen,Ai‐Li Shiau,Cheng Yang Chou
出处
期刊:Autophagy
[Informa]
日期:2009-05-16
卷期号:5 (4): 451-460
被引量:135
标识
DOI:10.4161/auto.5.4.7666
摘要
Cathepsins have long been considered as housekeeping molecules. However, specific functions have also been attributed to each one of these lysosomal proteases. Squamous cell carcinoma antigen (SCCA) 1, widely expressed in various uterine cervical cells, is an endogenous cathepsin (cat) L inhibitor. In this study, we investigated whether the cat L-SCCA 1 lysosomal pathway and autophagy were involved in resveratrol (RSV)-induced cytotoxicity in cervical cancer cells. RSV induced GFP-LC3 aggregation as well as increased the presence of LC3-II and autophagosomes as was revealed by electron microscopy in cervical cancer cells. Prolonged treatment of RSV induced cytosolic translocation of cytochrome c, caspase 3 activation, and apoptotic cell death. This apoptotic effect was abrogated by trans-epoxysuccinyl- L-leucylamido - (4-guanidino)butane, an inhibitor of cat B and L, but not by pepstatin A, an inhibitor of cat D. As cervical cancer cells express little cat B, we further studied the role of cat L. RSV induced dissipation of the lysosomal membrane permeability (LMP), leakage and increased cytosolic expression and activity of cat L. Inhibition of cat L by small interference RNA (siRNA) protected cells from RSV-induced cytotoxicity. In contrast, inhibition of SCCA 1 by siRNA promoted RSV-induced cytotoxicity. Inhibition of autophagic response by wormannin (WT) or asparagine (ASP) resulted in decreased early LC3-II formation, reduced LMP, and abolishment of the increase in RSV-induced cell death. In conclusion, we have identified a new cytotoxic mechanism in which the lysosomal enzyme cat L acts as a death signal integrator in cervical cancer cells. Furthermore, SCCA 1 may play an anti-apoptotic role through anti-cat L activity.
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