Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth.

Publication Type:

Journal Article

Authors:

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

Source:

Cancer Cell, Volume 22, Issue 5, p.585-600 (2012)

Keywords:

Animals, Binding, Competitive, Cell Line, Tumor, Cell Proliferation, Enzyme Activation, Gene Knockdown Techniques, Gluconates, Glucosephosphate Dehydrogenase, Glyceric Acids, Glycolysis, Humans, Mice, Mice, Nude, Models, Molecular, Neoplasms, Phosphoglycerate Mutase

Abstract:

<p>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.</p>