title: TIGAR has a dual role in cancer cell survival through regulating apoptosis and autophagy.
abstract: The p53-induced glycolysis and apoptosis regulator (TIGAR) inhibits glycolysis, resulting in higher intracellular NADPH, lower reactive oxygen species (ROS) and autophagy activity. In this study, we investigated whether TIGAR might exert dual impacts on cancer cell survival based on its ability to inhibit both apoptosis and autophagy. In liver or lung cancer cells treated with the anticancer drug epirubicin, TIGAR levels increased in a dose- and time-dependent manner. TIGAR silencing enhanced epirubicin-induced elevations in ROS levels and apoptosis rates, in a manner that was blocked by ectopic addition of NADPH or N-acetyl cysteine. These findings were correlated with reduced tumorigenicity and increased chemosensitivity in mouse xenograft tumor assays. In parallel, TIGAR silencing also enhanced the epirubicin-induced activation of autophagy, in a manner that was also blocked by ectopic addition of NADPH. Notably, TIGAR silencing also licensed epirubicin-mediated inactivation of the mTOR pathway, suggesting TIGAR also exerted a negative impact on autophagy. However, genetic or pharmacologic inhibition of autophagy increased epirubicin-induced apoptosis in TIGAR-silenced cells. Overall, our results revealed that TIGAR inhibits both apoptosis and autophagy, resulting in a dual impact on tumor cell survival in response to tumor chemotherapy. Cancer Res; 74(18); 5127-38. ©2014 AACR.
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Jia-Ming
authors.initials: JM
authors.lastname: Xie
authors.affiliation: Department of General Surgery, The First Hospital of Wu Jiang, Suzhou, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Hong-Pei
authors.initials: HP
authors.lastname: Yu
authors.affiliation: Department of General Surgery, The First Hospital of Wu Jiang, Suzhou, China.
authors.forename: Quan-Geng
authors.initials: QG
authors.lastname: Gao
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China. wuhaorong@vip.sina.com qinzhenhong@suda.edu.cn.
authors.forename: Hao-Rong
authors.initials: HR
authors.lastname: Wu
authors.affiliation: Department of Pharmacology and Laboratory of Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Soochow University School of Pharmaceutical Science, Suzhou, China. wuhaorong@vip.sina.com qinzhenhong@suda.edu.cn.
authors.forename: Zheng-Hong
authors.initials: ZH
authors.lastname: Qin
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D015251:Epirubicin / Q000494:pharmacology; D005260:Female; D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D064593:Heterografts; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D010744:Phosphoric Monoester Hydrolases; D014162:Transfection
chemical_list: D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015251:Epirubicin; D010744:Phosphoric Monoester Hydrolases; C512708:TIGAR protein, human