title: Hypoxia attenuates Hsp90 inhibitor 17-DMAG-induced cyclin B1 accumulation in hepatocellular carcinoma cells.
abstract: Hypoxia stress plays a pivotal role in tumor formation, proliferation, and invasion. Conventional chemotherapy is less effective in the hypoxia microenvironment of solid tumor. Heat shock protein 90 (Hsp90) is an important molecular chaperone in cancer cells and has been a pharmaceutical target for decades. However, Hsp90 inhibitors demonstrate limited effect on solid tumor and the mechanism underlying is not clear. To determine whether hypoxia impairs the therapeutic effect of Hsp90 N-terminal inhibitor, 17-demethoxygeldanamycin hydrochloride (17-DMAG), in live cancer cells, we measured cell proliferation and cell cycle distribution. Cell proliferation assay indicates that hypoxia obviously promotes the proliferation of HepG2 and Huh7 cells after 24, 48, and 72 h and impairs 17-DMAG-induced G2/M arrest in liver cancer cells. As a client protein of Hsp90, cyclin B1 is critical for the transition from G2 to M phase and is related to the prognosis of the patients. We further checked the cyclin B1 messenger RNA (mRNA) level, protein level, ubiquitination of cyclin B1, nuclear translocation, and degradation of cyclin B1 affected by hypoxia after 17-DMAG treatment. The results demonstrate that hypoxia decreases the transcription of cyclin B1 and accelerates the ubiquitination, nuclear translocation, and degradation of cyclin B1. Taken together, our results suggest that hypoxia attenuates cyclin B1 accumulation induced by 17-DMAG and, hence, alleviates 17-DMAG-induced G2/M arrest.
authors.affiliation: Department of Occupational Health and Medicine, School of Public Health and Tropical Medicine, Southern Medical University, 1838 Guangzhou Road North, Guangzhou, 510515, China.
authors.forename: Jianming
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Occupational Health and Medicine, School of Public Health and Tropical Medicine, Southern Medical University, 1838 Guangzhou Road North, Guangzhou, 510515, China.
authors.forename: Huadan
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Occupational Health and Medicine, School of Public Health and Tropical Medicine, Southern Medical University, 1838 Guangzhou Road North, Guangzhou, 510515, China.
authors.forename: Zhizhou
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Occupational Health and Medicine, School of Public Health and Tropical Medicine, Southern Medical University, 1838 Guangzhou Road North, Guangzhou, 510515, China.
authors.forename: Yangfan
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Occupational Health and Medicine, School of Public Health and Tropical Medicine, Southern Medical University, 1838 Guangzhou Road North, Guangzhou, 510515, China.
authors.forename: Xueqiong
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Occupational Health and Medicine, School of Public Health and Tropical Medicine, Southern Medical University, 1838 Guangzhou Road North, Guangzhou, 510515, China.
authors.forename: Tingyuan
authors.initials: T
authors.lastname: Huang
authors.affiliation: Department of Occupational Health and Medicine, School of Public Health and Tropical Medicine, Southern Medical University, 1838 Guangzhou Road North, Guangzhou, 510515, China.
authors.forename: Peijuan
authors.initials: P
authors.lastname: Dai
authors.affiliation: Department of Occupational Health and Medicine, School of Public Health and Tropical Medicine, Southern Medical University, 1838 Guangzhou Road North, Guangzhou, 510515, China.
authors.forename: Danping
authors.initials: D
authors.lastname: Duan
authors.affiliation: Department of Occupational Health and Medicine, School of Public Health and Tropical Medicine, Southern Medical University, 1838 Guangzhou Road North, Guangzhou, 510515, China.
authors.forename: Xiaojiao
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Occupational Health and Medicine, School of Public Health and Tropical Medicine, Southern Medical University, 1838 Guangzhou Road North, Guangzhou, 510515, China.
authors.forename: Qiangbin
authors.initials: Q
authors.lastname: Yin
authors.affiliation: Department of Occupational Health and Medicine, School of Public Health and Tropical Medicine, Southern Medical University, 1838 Guangzhou Road North, Guangzhou, 510515, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Occupational Health and Medicine, School of Public Health and Tropical Medicine, Southern Medical University, 1838 Guangzhou Road North, Guangzhou, 510515, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, 19 Nonglinxia Road, Guangzhou, 510080, China.
authors.forename: Size
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Occupational Health and Medicine, School of Public Health and Tropical Medicine, Southern Medical University, 1838 Guangzhou Road North, Guangzhou, 510515, China. zfei@smu.edu.cn.
authors.forename: Fei
authors.initials: F
authors.lastname: Zou
authors.affiliation: Department of Occupational Health and Medicine, School of Public Health and Tropical Medicine, Southern Medical University, 1838 Guangzhou Road North, Guangzhou, 510515, China. cxmcsz@smu.edu.cn.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000150:complications* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056744:Cyclin B1 / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D056744:Cyclin B1; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
keywords: 17-DMAG; Cell cycle arrest; Chemoresistance; Cyclin B1; Hypoxia