title: Heat shock protein 70 silencing enhances apoptosis inducing factor-mediated cell death in hepatocellular carcinoma HepG2 cells.
abstract: Heat shock protein 70 (HSP70) abundantly expressed in human tumors and protects cells from a wide range of apoptotic stimuli. To study the role of HSP70 in human hepatocarcinomas, we stably silenced HSP70 gene expression in HepG(2) cells by transfecting the cells with HSP70-silencing vector (HSP70 shRNA). HSP70 silencing resulted in reduced capacities for cell proliferation in vitro and colony formation in soft agar. In addition, HSP70 silencing enhanced chemotherapy drug-induced cell death and tumor growth in a mouse xenograft model. Most importantly, we extended our previous observation that HSP70 modulates mitochondrial protein Apoptosis-inducing factor (AIF)-induced cell death. In this study, we found that HSP70 silencing dramatically increased AIFDelta1-120 mutant (an active form of AIF after deletion of the mitochondria localization domain)-induced apoptosis. In HSP70 silenced cells, AIFDelta1-120 mutant predominantly localized in nuclear compartment compared to the control cells, confirming that HSP70 protects from apoptosis by sequestering AIF in the cytoplasm. Taken together, our data suggest that HSP70 ablation in combination with delivery of AIFDelta1-120 mutant or other chemotherapy drugs represents a potent anti-cancer therapy for hepatocarcinomas.
authors.affiliation: Department of Medical Oncology, The First Affiliated Hospital, Xi'an Jiaotong University Collage of Medicine, 17 Chanle West Road, Xi'an, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhu
authors.forename: Yan-Ming
authors.initials: YM
authors.lastname: Xu
authors.forename: Li-Feng
authors.initials: LF
authors.lastname: Wang
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Lin-Tao
authors.initials: LT
authors.lastname: Jia
authors.forename: Wang-Gang
authors.initials: WG
authors.lastname: Zhang
authors.forename: An-Gang
authors.initials: AG
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051033:Apoptosis Inducing Factor / Q000235:genetics* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D020868:Gene Silencing; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D051033:Apoptosis Inducing Factor; D018840:HSP70 Heat-Shock Proteins; D034741:RNA, Small Interfering