Transketolase Deficiency Protects the Liver from DNA Damage by Increasing Levels of Ribose 5-Phosphate and Nucleotides
| Autor: | Tianle Xu, Lingfeng Tong, Ying Lu, Minle Li, Xuemei Tong, Xiao-chuan Gu, Jian Meng, Lifang Wu, Ming Feng, Ping Zhang, Shuhai Lin, Yemin Zhu, Yakui Li, Na Tian |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Genome instability Male Cancer Research Programmed cell death DNA damage Pentose phosphate pathway Transketolase Pentose Phosphate Pathway 03 medical and health sciences Mice 0302 clinical medicine Liver Neoplasms Experimental medicine Animals Diethylnitrosamine Liver injury Mice Knockout Chemistry Cell growth Nucleotides medicine.disease Molecular biology Mice Inbred C57BL 030104 developmental biology Oncology Liver Apoptosis 030220 oncology & carcinogenesis Ribosemonophosphates Glycolysis DNA Damage |
| Zdroj: | Cancer research. 79(14) |
| ISSN: | 1538-7445 |
| Popis: | De novo nucleotide biosynthesis is essential for maintaining cellular nucleotide pools, the suppression of which leads to genome instability. The metabolic enzyme transketolase (TKT) in the nonoxidative branch of the pentose phosphate pathway (PPP) regulates ribose 5-phosphate (R5P) levels and de novo nucleotide biosynthesis. TKT is required for maintaining cell proliferation in human liver cancer cell lines, yet the role of TKT in liver injury and cancer initiation remains to be elucidated. In this study, we generated a liver-specific TKT knockout mouse strain by crossing TKTflox/flox mice with albumin-Cre mice. Loss of TKT in hepatocytes protected the liver from diethylnitrosamine (DEN)-induced DNA damage without altering DEN metabolism. DEN treatment of TKT-null liver increased levels of R5P and promoted de novo nucleotide synthesis. More importantly, supplementation of dNTPs in primary hepatocytes alleviated DEN-induced DNA damage, cell death, inflammatory response, and cell proliferation. Furthermore, DEN and high-fat diet (HFD)–induced liver carcinogenesis was reduced in TKTflox/floxAlb-Cre mice compared with control littermates. Mechanistically, loss of TKT in the liver increased apoptosis, reduced cell proliferation, decreased TNFα, IL6, and STAT3 levels, and alleviated DEN/HFD-induced hepatic steatosis and fibrosis. Together, our data identify a key role for TKT in promoting genome instability during liver injury and tumor initiation. Significance: These findings identify transketolase as a novel metabolic target to maintain genome stability and reduce liver carcinogenesis. |
| Databáze: | OpenAIRE |
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