title: Knockdown of malic enzyme 2 suppresses lung tumor growth, induces differentiation and impacts PI3K/AKT signaling.
abstract: Mitochondrial 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.
authors: 1] Divisions of Interdisciplinary Medicine and Biotechnology, Hematology-Oncology and Nephrology, Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215 [2].
authors: Jian-Guo
authors: JG
authors: Ren
authors: 1] Divisions of Interdisciplinary Medicine and Biotechnology, Hematology-Oncology and Nephrology, Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215 [2].
authors: Pankaj
authors: P
authors: Seth
authors: Metabolite Profiling Initiative, The Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142.
authors: Clary B
authors: CB
authors: Clish
authors: 1] Center for Regulatory and Environmental Analytical Metabolomics [2] Department of Chemistry, University of Louisville, Louisville, KY 40208.
authors: Pawel K
authors: PK
authors: Lorkiewicz
authors: 1] Center for Regulatory and Environmental Analytical Metabolomics [2] Department of Chemistry, University of Louisville, Louisville, KY 40208.
authors: Richard M
authors: RM
authors: Higashi
authors: 1] Center for Regulatory and Environmental Analytical Metabolomics [2] J. G. Brown Cancer Center, University of Louisville, Louisville, KY 40208.
authors: Andrew N
authors: AN
authors: Lane
authors: 1] Center for Regulatory and Environmental Analytical Metabolomics [2] Department of Chemistry, University of Louisville, Louisville, KY 40208 [3] J. G. Brown Cancer Center, University of Louisville, Louisville, KY 40208.
authors: Teresa W-M
authors: TW
authors: Fan
authors: Divisions of Interdisciplinary Medicine and Biotechnology, Hematology-Oncology and Nephrology, Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215.
authors: Vikas P
authors: VP
authors: Sukhatme
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D008291:Malate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D008293:Malates / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D055815:Young Adult
chemical_list: D008293:Malates; D008291:Malate Dehydrogenase; C495394:malic enzyme 2; human; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt