You are here

Sci Rep DOI:10.1038/srep05414

Knockdown of malic enzyme 2 suppresses lung tumor growth, induces differentiation and impacts PI3K/AKT signaling.

Publication TypeJournal Article
Year of Publication2014
AuthorsRen, J-G, Seth, P, Clish, CB, Lorkiewicz, PK, Higashi, RM, Lane, AN, Fan, TW-M, Sukhatme, VP
JournalSci Rep
Volume4
Pages5414
Date Published2014 Jun 24
ISSN2045-2322
KeywordsAdolescent, Adult, Aged, Aged, 80 and over, Animals, Blotting, Western, Cell Differentiation, Cell Line, Tumor, Cell Proliferation, Child, Child, Preschool, Female, Humans, Lung Neoplasms, Malate Dehydrogenase, Malates, Male, Mice, Nude, Middle Aged, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, RNA Interference, Signal Transduction, Xenograft Model Antitumor Assays, Young Adult
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.

URLhttp://dx.doi.org/10.1038/srep05414
DOI10.1038/srep05414
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24957098?dopt=Abstract

Alternate JournalSci Rep
PubMed ID24957098
PubMed Central IDPMC4067620
Grant ListP01 CA163223 / CA / NCI NIH HHS / United States
T32 DK007199 / DK / NIDDK NIH HHS / United States
5R01CA15233 / CA / NCI NIH HHS / United States