@article{488f85cf1c304173911bf12b8f9147cd,
title = "Conversion of prps hexamer to monomer by AMPK-mediated phosphorylation inhibits nucleotide synthesis in response to energy stress",
abstract = "Tumors override energy stress to grow. However, how nucleotide synthesis is regulated under energy stress is unclear. We demonstrate here that glucose dep- rivation 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. SIGNIFICANCE: Our findings elucidate an instrumental function of AMPK in direct regulation of nucleic acid and NAD synthesis in tumor cells in response to energy stress. AMPK phosphorylates PRPS1/2, converts PRPS1/2 hexamers to monomers, and inhibits PRPS1/2 activity and subsequent nucleotide and NAD synthesis to maintain tumor cell growth and survival.",
author = "Xu Qian and Xinjian Li and Lin Tan and Lee, {Jong Ho} and Yan Xia and Qingsong Cai and Yanhua Zheng and Hongxia Wang and Lorenzi, {Philip L.} and Zhimin Lu",
note = "Funding Information: This work was supported by National Institute of Neurological Disorders and Stroke grant R01 NS089754 (Z. Lu), National Cancer Institute grants 2R01 CA109035 (Z. Lu) and R01 CA169603 (Z. Lu), 2P50 CA127001 (Brain Cancer SPORE), MD Anderson{\textquoteright}s Cancer Center Support Grant CA016672, and the National Natural Science Foundation of China (NSFC) 816228011 (H. Wang), 81572499, and 81572700. Z. Lu is a Ruby E. Rutherford Distinguished Professor. Funding Information: We thank Dr. Li Li (Clinical and Translational Proteomics Service Center, Institute of Molecular Medicine, The University of Texas Health Center at Houston) for technical assistance, and Ann Sutton (The University of Texas MD Anderson Cancer Center) for her critical reading of the manuscript.This work was supported by National Institute of Neurological Disorders and Stroke grant R01 NS089754 (Z. Lu), National Cancer Institute grants 2R01 CA109035 (Z. Lu) and R01 CA169603 (Z. Lu), 2P50 CA127001 (Brain Cancer SPORE), MD Anderson{\textquoteright}s Cancer Center Support Grant CA016672, and the National Natural Science Foundation of China (NSFC) 816228011 (H. Wang), 81572499, and 81572700. Z. Lu is a Ruby E. Rutherford Distinguished Professor. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Publisher Copyright: {\textcopyright} 2017 American Association for Cancer Research.",
year = "2018",
month = jan,
doi = "10.1158/2159-8290.CD-17-0712",
language = "English (US)",
volume = "8",
pages = "94--107",
journal = "Cancer discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "1",
}