[PDF][PDF] Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth

T Hitosugi, L Zhou, S Elf, J Fan, HB Kang, JH Seo… - Cancer cell, 2012 - cell.com
T Hitosugi, L Zhou, S Elf, J Fan, HB Kang, JH Seo, C Shan, Q Dai, L Zhang, J Xie, TL Gu…
Cancer cell, 2012cell.com
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) …
Summary
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.
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