Pharmaceutical Sciences Faculty Publications

Title

Pyruvate Kinase M2 is a Target of the Tumorsuppressive MicroRNA-326 and Regulates the Survival of Glioma Cells

Document Type

Article

Publication Date

11-2010

Journal Title

Neuro-Oncology

ISSN

1523-5866

Volume

12

Issue

11

First Page

1102

Last Page

1112

DOI

http://dx.doi.org/10.1093/neuonc/noq080

PubMed ID

20667897

PubMed Central® ID

PMC3098027

Abstract

Emerging studies have identified microRNAs (miRNAs) as possible therapeutic tools for the treatment of glioma, the most aggressive brain tumor. Their important targets in this tumor are not well understood. We recently found that the Notch pathway is a target of miRNA-326. Ectopic expression of miRNA-326 in glioma and glioma stem cells induced their apoptosis and reduced their metabolic activity. Computational target gene prediction revealed pyruvate kinase type M2 (PKM2) as another target of miRNA-326. PKM2 has recently been shown to play a key role in cancer cell metabolism. To investigate whether it might be a functionally important target of miR-326, we used RNA interference to knockdown PKM2 expression in glioma cells. Transfection of the established glioma and glioma stem cells with PKM2 siRNA reduced their growth, cellular invasion, metabolic activity, ATP and glutathione levels, and activated AMP-activated protein kinase. The cytotoxic effects exhibited by PKM2 knockdown in glioma and glioma stem cells were not observed in transformed human astrocytes. Western blot analysis of human glioblastoma specimens showed high levels of PKM2 protein, but none was observed in normal brain samples. Strikingly, cells with high levels of PKM2 expressed lower levels of miR-326, suggestive of endogenous regulation of PKM2 by miR-326. Our data suggest PKM2 inhibition as a therapy for glioblastoma, with the potential for minimal toxicity to the brain.

Keywords

AMP-activated protein kinase, brain tumor, glioma, microRNA, microRNA-326, pyruvate kinase M2, tumor stem cells