title: Transketolase counteracts oxidative stress to drive cancer development.
abstract: Cancer cells experience an increase in oxidative stress. The pentose phosphate pathway (PPP) is a major biochemical pathway that generates antioxidant NADPH. Here, we show that transketolase (TKT), an enzyme in the PPP, is required for cancer growth because of its ability to affect the production of NAPDH to counteract oxidative stress. We show that TKT expression is tightly regulated by the Nuclear Factor, Erythroid 2-Like 2 (NRF2)/Kelch-Like ECH-Associated Protein 1 (KEAP1)/BTB and CNC Homolog 1 (BACH1) oxidative stress sensor pathway in cancers. Disturbing the redox homeostasis of cancer cells by genetic knockdown or pharmacologic inhibition of TKT sensitizes cancer cells to existing targeted therapy (Sorafenib). Our study strengthens the notion that antioxidants are beneficial to cancer growth and highlights the therapeutic benefits of targeting pathways that generate antioxidants.
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, SAR, China;
authors.forename: Iris Ming-Jing
authors.initials: IM
authors.lastname: Xu
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, SAR, China;
authors.forename: Robin Kit-Ho
authors.initials: RK
authors.lastname: Lai
authors.affiliation: Department of Chemistry,Hong Kong Baptist University, Hong Kong, SAR, China; State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong, SAR, China;
authors.forename: Shu-Hai
authors.initials: SH
authors.lastname: Lin
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, SAR, China;
authors.forename: Aki Pui-Wah
authors.initials: AP
authors.lastname: Tse
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, SAR, China;
authors.forename: David Kung-Chun
authors.initials: DK
authors.lastname: Chiu
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, SAR, China;
authors.forename: Hui-Yu
authors.initials: HY
authors.lastname: Koh
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, SAR, China;
authors.forename: Cheuk-Ting
authors.initials: CT
authors.lastname: Law
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, SAR, China; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, SAR, China.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Wong
authors.affiliation: Department of Chemistry,Hong Kong Baptist University, Hong Kong, SAR, China; State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong, SAR, China;
authors.forename: Zongwei
authors.initials: Z
authors.lastname: Cai
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, SAR, China; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, SAR, China iolng@hku.hk carmencl@pathology.hku.hk.
authors.forename: Carmen Chak-Lui
authors.initials: CC
authors.lastname: Wong
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, SAR, China; State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, SAR, China iolng@hku.hk carmencl@pathology.hku.hk.
authors.forename: Irene Oi-Lin
authors.initials: IO
authors.lastname: Ng
mesh_terms: D000818:Animals; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology; D008297:Male; D055442:Metabolome / Q000187:drug effects; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010427:Pentose Phosphate Pathway / Q000187:drug effects; D010545:Peroxides / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000077157:Sorafenib; D014174:Transketolase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D010545:Peroxides; D010671:Phenylurea Compounds; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D009536:Niacinamide; D000077157:Sorafenib; D014174:Transketolase; D005978:Glutathione; D005947:Glucose; C000602361:tert-butyl peroxide
keywords: HCC; PPP; ROS; TKT; metabolism
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