Metabolic Signaling and Therapy of Lung Cancer
Annual rept. 1 Sep 2012-31 Aug 2013
EMORY UNIV ATLANTA GA
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The purpose of this grant is to decipher molecular mechanisms by which glycolytic enzyme phosphoglycerate mutase 1 PGAM1 promotes lung cancer cell metabolism and evaluate novel PGAM1 inhibitors as anti-cancer therapy in treatment of lung cancer. We accomplished studies for Month 1-12 as proposed in the approved Statement of Work. We published a featured article in Cancer Cell and demonstrated that PGAM1 is commonly upregulated in human cancers including lung cancer due to loss of TP53 and is important to coordinate glycolysis and biosynthesis in cancer cells. We developed a novel small molecule PGAM inhibitor PGMI-004A. Inhibition of PGAM1 by shRNA or PGMI-004A results in significantly decreased glycolysis, pentose phosphate pathway flux and biosynthesis in lung cancer cells, as well as attenuated cell proliferation and tumor growth, suggesting PGAM1 as a promising target in treatment of lung cancer. Moreover, in a recent Nature Communications paper, we reported a novel mechanism in which Y26 phosphorylation activates PGAM1 to promote lung cancer cell proliferation and tumor growth. In addition, we now show that EGFR phosphorylates and activates PGAM1 by promoting cofactor 2,3- BPG binding in lung cancer cells and generated rescue PGAM1 WT and Y26F stable cell lines using different lung cancer cell lines.
- Medicine and Medical Research