Ren, Jian-GuoSeth, PankajClish, Clary B.Lorkiewicz, Pawel K.Higashi, Richard M.Lane, Andrew N.Fan, Teresa W.-M.Sukhatme, Vikas2014-07-072014Ren, Jian-Guo, Pankaj Seth, Clary B. Clish, Pawel K. Lorkiewicz, Richard M. Higashi, Andrew N. Lane, Teresa W.-M. Fan, and Vikas P. Sukhatme. 2014. “Knockdown of Malic Enzyme 2 Suppresses Lung Tumor Growth, Induces Differentiation and Impacts PI3K/AKT Signaling.” Scientific Reports 4 (1): 5414. doi:10.1038/srep05414. http://dx.doi.org/10.1038/srep05414.2045-2322http://nrs.harvard.edu/urn-3:HUL.InstRepos:12406737Mitochondrial malic enzyme 2 (ME2) catalyzes the oxidative decarboxylation of malate to yield CO2 and pyruvate, with concomitant reduction of dinucleotide cofactor NAD+ or NADP+. We find that ME2 is highly expressed in many solid tumors. In the A549 non-small cell lung cancer (NSCLC) cell line, ME2 depletion inhibits cell proliferation and induces cell death and differentiation, accompanied by increased reactive oxygen species (ROS) and NADP+/NADPH ratio, a drop in ATP, and increased sensitivity to cisplatin. ME2 knockdown impacts phosphoinositide-dependent protein kinase 1 (PDK1) and phosphatase and tensin homolog (PTEN) expression, leading to AKT inhibition. Depletion of ME2 leads to malate accumulation and pyruvate decrease, and exogenous cell permeable dimethyl-malate (DMM) mimics the ME2 knockdown phenotype. Both ME2 knockdown and DMM treatment reduce A549 cell growth in vivo. Collectively, our data suggest that ME2 is a potential target for cancer therapy.en-USJournal Article2014-07-0710.1038/srep05414