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

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, Masa Alečković, Gary LeRoy, Yibin Kang, Jessica A Sudderth, Ralph J DeBerardinis, Chi-Hao Luan, Georgia Z Chen, Susan Muller, Dong M Shin, Taofeek K Owonikoko, Sagar Lonial, Martha L Arellano, Hanna J Khoury, Fadlo R Khuri, Benjamin H Lee, Keqiang Ye, Titus J Boggon, Sumin Kang, Chuan He, Jing Chen

Index: Cancer Cell 22(5) , 585-600, (2012)

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Abstract

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.Copyright © 2012 Elsevier Inc. All rights reserved.