Scientific Publications

Knockdown of Malic Enzyme 2 Suppresses Lung Tumor Growth, Induces Differentiation and Impacts PI3K/AKT Signaling.

Publication TypeJournal Article
AuthorsRen, JG, Seth P., Clish CB, Lorkiewicz PK, Higashi RM, Lane AN, Fan TW, and Sukhatme VP
AbstractMitochondrial 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.
Year of Publication2014
JournalScientific reports
Volume4
Pages5414
Date Published (YYYY/MM/DD)2014/06/24
DOI10.1038/srep05414
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/24957098?dopt=Abstract