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Phosphoglycerate Mutase 1 Coordinates Glycolysis and Biosynthesis to Promote Tumor Growth

2012; Cell Press; Volume: 22; Issue: 5 Linguagem: Inglês

10.1016/j.ccr.2012.09.020

1878-3686

Taro Hitosugi, Lu Zhou, Shannon Elf, Jun Fan, Hee‐Bum Kang, Jae Ho Seo, Changliang Shan, Qing Dai, Liang Zhang, Jianxin Xie, Ting-Lei Gu, Peng Jin, Maša Alečković, Gary LeRoy, Yibin Kang, Jessica Sudderth, Ralph J. DeBerardinis, Chi Hao Luan, Georgia Z. Chen, Susan J. Muller, Dong M. Shin, Taofeek K. Owonikoko, Sagar Lonial, Martha Arellano, H. Jean Khoury, Fadlo R. Khuri, Benjamin H. Lee, Keqiang Ye, Titus J. Boggon, Sumin Kang, Chuan He, Jing Chen,

Cancer-related Molecular Pathways

It is unclear how cancer cells coordinate glycolysis and biosynthesis to support rapidly growing tumors. We found that the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1), commonly upregulated in human cancers due to loss of TP53, contributes to biosynthesis regulation in part by controlling intracellular levels of its substrate, 3-phosphoglycerate (3-PG), and product, 2-phosphoglycerate (2-PG). 3-PG binds to and inhibits 6-phosphogluconate dehydrogenase in the oxidative pentose phosphate pathway (PPP), while 2-PG activates 3-phosphoglycerate dehydrogenase to provide feedback control of 3-PG levels. Inhibition of PGAM1 by shRNA or a small molecule inhibitor PGMI-004A results in increased 3-PG and decreased 2-PG levels in cancer cells, leading to significantly decreased glycolysis, PPP flux and biosynthesis, as well as attenuated cell proliferation and tumor growth.