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

Jian Guo Ren, Pankaj Seth, Clary B. Clish, Pawel K. Lorkiewicz, Richard M. Higashi, Andrew N. Lane, Teresa W.M. Fan, Vikas P. Sukhatme

Research output: Contribution to journalArticlepeer-review

66 Scopus citations


Mitochondrial malic enzyme 2 (ME2) catalyzes the oxidative decarboxylation of malate to yield CO 2 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.

Original languageEnglish
Article number5414
JournalScientific Reports
StatePublished - Jun 24 2014

Bibliographical note

Funding Information:
This work was supported by seed funds from BIDMC to VPS, and an NIDDK training grant to VPS (NIH T32 DK007199) that was used to support JGR. Some data was generated using support from a subaward to VPS from NCI-SAIC-Fredericks (S080221 TO10) and NIH 5R01CA15233 to PS. The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

ASJC Scopus subject areas

  • General


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