期刊
CANCER DISCOVERY
卷 8, 期 1, 页码 94-107出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-17-0712
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资金
- National Institute of Neurological Disorders and Stroke [R01 NS089754]
- National Cancer Institute [2R01 CA109035, R01 CA169603]
- Brain Cancer SPORE [2P50 CA127001]
- MD Anderson's Cancer Center Support Grant [CA016672]
- National Natural Science Foundation of China (NSFC) [816228011, 81572499, 81572700]
Tumors override energy stress to grow. However, how nucleotide synthesis is regulated under energy stress is unclear. We demonstrate here that glucose deprivation or hypoxia results in the AMPK-mediated phosphorylation of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) S180 and PRPS2 S183, leading to conversion of PRPS hexamers to monomers and thereby inhibiting PRPS1/2 activity, nucleotide synthesis, and nicotinamide adenine dinucleotide (NAD) production. Knock-in of nonphosphorylatable PRPS1/2 mutants, which have uninhibited activity, in brain tumor cells under energy stress exhausts cellular ATP and NADPH and increases reactive oxygen species levels, thereby promoting cell apoptosis. The expression of those mutants inhibits brain tumor formation and enhances the inhibitory effect of the glycolysis inhibitor 2-deoxy-D-glucose on tumor growth. Our findings highlight the significance of recalibrating tumor cell metabolism by fine-tuning nucleotide and NAD synthesis in tumor growth. (c) 2017 AACR.
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