AMPK reverses the mesenchymal phenotype of cancer cells by targeting the Akt-MDM2-Foxo3a signaling axis

Chih Chien Chou, Kuen Haur Lee, I. Lu Lai, Dasheng Wang, Xiaokui Mo, Samuel K. Kulp, Charles L. Shapiro, Ching Shih Chen

Research output: Contribution to journalArticle

99 Citations (Scopus)

Abstract

In cancer cells, the epithelial-mesenchymal transition (EMT) confers the ability to invade basement membranes and metastasize to distant sites, establishing it as an appealing target for therapeutic intervention. Here, we report a novel function of the master metabolic kinase AMPK in suppressing EMT by modulating the Akt-MDM2-Foxo3 signaling axis. This mechanistic link was supported by the effects of siRNA-mediated knockdown and pharmacologic activation of AMPK on epithelial and mesenchymal markers in established breast and prostate cancer cells. Exposure of cells to OSU-53, a novel allosteric AMPK activator, as well as metformin and AICAR, was sufficient to reverse their mesenchymal phenotype. These effects were abrogated by AMPK silencing. Phenotypic changes were mediated by Foxo3a activation, insofar as silencing or overexpressing Foxo3a mimicked the effects of AMPK silencing or OSU-53 treatment on EMT, respectively. Mechanistically, Foxo3a activation led to the transactivation of the E-cadherin gene and repression of genes encoding EMT-inducing transcription factors. OSU-53 activated Foxo3a through two Akt-dependent pathways, one at the level of nuclear localization by blocking Akt- and IKKb-mediated phosphorylation, and a second at the level of protein stabilization via cytoplasmic sequestration of MDM2, an E3 ligase responsible for Foxo3a degradation. The suppressive effects of OSU-53 on EMT had therapeutic implications illustrated by its ability to block invasive phenotypes in vitro and metastatic properties in vivo. Overall, our work illuminates a mechanism of EMT regulation in cancer cells mediated by AMPK, along with preclinical evidence supporting a tractable therapeutic strategy to reverse mesenchymal phenotypes associated with invasion and metastasis.

Original languageEnglish
Pages (from-to)4783-4795
Number of pages13
JournalCancer Research
Volume74
Issue number17
DOIs
Publication statusPublished - Sep 1 2014

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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    Chou, C. C., Lee, K. H., Lai, I. L., Wang, D., Mo, X., Kulp, S. K., Shapiro, C. L., & Chen, C. S. (2014). AMPK reverses the mesenchymal phenotype of cancer cells by targeting the Akt-MDM2-Foxo3a signaling axis. Cancer Research, 74(17), 4783-4795. https://doi.org/10.1158/0008-5472.CAN-14-0135