Transketolase counteracts oxidative stress to drive cancer development
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...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 6; pp. E725 - E734 |
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| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
09.02.2016
National Acad Sciences |
| Series | PNAS Plus |
| Subjects | |
| Online Access | Get full text |
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| 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. |
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| AbstractList | 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. Excessive accumulation of oxidative stress is harmful to cancer cells. Our study demonstrates the important roles of a pentose phosphate pathway (PPP) enzyme, transketolase (TKT), in redox homeostasis in cancer development. We highlight the clinical relevance of TKT expression in cancers. We also show that TKT overexpression in cancer cells is a response of Nuclear Factor, Erythroid 2-Like 2 (NRF2) activation, a sensor to cellular oxidative stress. TKT locates at an important position that connects PPP with glycolysis to affect production of antioxidant NADPH. Our preclinical study shows that targeting TKT leads to elevation of oxidative stress, making cancer cells more vulnerable to therapeutic treatment, such as Sorafenib. Using TKT as an example, our study suggests that targeting enzymes for antioxidant production represents a direction for cancer treatment. 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. |
| Author | Xu, Iris Ming-Jing Wong, Chun-Ming Tse, Aki Pui-Wah Wong, Carmen Chak-Lui Cai, Zongwei Law, Cheuk-Ting Lin, Shu-Hai Koh, Hui-Yu Chiu, David Kung-Chun Ng, Irene Oi-Lin Lai, Robin Kit-Ho |
| Author_xml | – sequence: 1 givenname: Iris Ming-Jing surname: Xu fullname: Xu, Iris Ming-Jing organization: Department of Pathology, The University of Hong Kong, Hong Kong, SAR, China – sequence: 2 givenname: Robin Kit-Ho surname: Lai fullname: Lai, Robin Kit-Ho organization: Department of Pathology, The University of Hong Kong, Hong Kong, SAR, China – sequence: 3 givenname: Shu-Hai surname: Lin fullname: Lin, Shu-Hai organization: State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong, SAR, China – sequence: 4 givenname: Aki Pui-Wah surname: Tse fullname: Tse, Aki Pui-Wah organization: Department of Pathology, The University of Hong Kong, Hong Kong, SAR, China – sequence: 5 givenname: David Kung-Chun surname: Chiu fullname: Chiu, David Kung-Chun organization: Department of Pathology, The University of Hong Kong, Hong Kong, SAR, China – sequence: 6 givenname: Hui-Yu surname: Koh fullname: Koh, Hui-Yu organization: Department of Pathology, The University of Hong Kong, Hong Kong, SAR, China – sequence: 7 givenname: Cheuk-Ting surname: Law fullname: Law, Cheuk-Ting organization: Department of Pathology, The University of Hong Kong, Hong Kong, SAR, China – sequence: 8 givenname: Chun-Ming surname: Wong fullname: Wong, Chun-Ming organization: State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, SAR, China – sequence: 9 givenname: Zongwei surname: Cai fullname: Cai, Zongwei organization: State Key Laboratory of Environmental and Biological Analysis, Hong Kong Baptist University, Hong Kong, SAR, China – sequence: 10 givenname: Carmen Chak-Lui surname: Wong fullname: Wong, Carmen Chak-Lui organization: State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, SAR, China – sequence: 11 givenname: Irene Oi-Lin surname: Ng fullname: Ng, Irene Oi-Lin organization: State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, SAR, China |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26811478$$D View this record in MEDLINE/PubMed |
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| Snippet | Cancer cells experience an increase in oxidative stress. The pentose phosphate pathway (PPP) is a major biochemical pathway that generates antioxidant NADPH.... Excessive accumulation of oxidative stress is harmful to cancer cells. Our study demonstrates the important roles of a pentose phosphate pathway (PPP) enzyme,... |
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| SubjectTerms | Animals Antioxidants Base Sequence Biological Sciences Cancer Carcinoma, Hepatocellular - enzymology Carcinoma, Hepatocellular - pathology Cell Cycle Checkpoints - drug effects Cell Death - drug effects Cell Line, Tumor Cell Proliferation - drug effects Cells Female Gene Knockdown Techniques Glucose - metabolism Glutathione - metabolism Glycolysis - drug effects Homeostasis Humans Liver Neoplasms - enzymology Liver Neoplasms - pathology Male Metabolome - drug effects Mice, Nude Molecular Sequence Data Niacinamide - analogs & derivatives Niacinamide - pharmacology Oxidative stress Oxidative Stress - drug effects Pentose Phosphate Pathway - drug effects Peroxides - pharmacology Phenylurea Compounds - pharmacology PNAS Plus Proteins Reactive Oxygen Species - metabolism RNA, Messenger - genetics RNA, Messenger - metabolism Sorafenib Transketolase - antagonists & inhibitors Transketolase - genetics Transketolase - metabolism Up-Regulation - drug effects |
| Title | Transketolase counteracts oxidative stress to drive cancer development |
| URI | https://www.jstor.org/stable/26467699 http://www.pnas.org/content/113/6/E725.abstract https://www.ncbi.nlm.nih.gov/pubmed/26811478 https://www.proquest.com/docview/1767703974 https://pubmed.ncbi.nlm.nih.gov/PMC4760787 |
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