TUFM downregulation induces epithelial-mesenchymal transition and invasion in lung cancer cells via a mechanism involving AMPK-GSK3β signaling

Cell Mol Life Sci. 2016 May;73(10):2105-21. doi: 10.1007/s00018-015-2122-9. Epub 2016 Jan 18.


Mitochondrial dysfunction and epithelial-to-mesenchymal transition (EMT) play important roles in cancer development and metastasis. However, very little is known about the connection between mitochondrial dysfunction and EMT. Tu translation elongation factor, mitochondrial (TUFM), a key factor in the translational expression of mitochondrial DNA, plays an important role in the control of mitochondrial function. Here, we show that TUFM is downregulated in human cancer tissues. TUFM expression level was positively correlated with that of E-cadherin and decreased significantly during the progression of human lung cancer. TUFM knockdown induced EMT, reduced mitochondrial respiratory chain activity, and increased glycolytic function and the production of reactive oxygen species (ROS). Mechanistically, TUFM knockdown activated AMPK and phosphorylated GSK3β and increased the nuclear accumulation of β-catenin, leading to the induction of EMT and increased migration and metastasis of A549 lung cancer cells. Although TUFM knockdown also induced EMT of MCF7 breast cancer cells, the underlying mechanism appeared somewhat different from that in lung cancer cells. Our work identifies TUFM as a novel regulator of EMT and suggests a molecular link between mitochondrial dysfunction and EMT induction.

Keywords: AMPK; EMT; Lung cancer; ROS; Signaling; TUFM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Cadherins / metabolism
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Disease Progression
  • Down-Regulation
  • Electron Transport
  • Epithelial-Mesenchymal Transition
  • Gene Expression Regulation, Neoplastic
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta
  • HEK293 Cells
  • Humans
  • Lung Neoplasms / pathology*
  • MCF-7 Cells
  • Mice
  • Mice, Nude
  • Mitochondria / pathology
  • Mitochondrial Proteins / metabolism*
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Peptide Elongation Factor Tu / metabolism*
  • Phosphorylation
  • Reactive Oxygen Species / metabolism
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • beta Catenin / metabolism


  • Cadherins
  • Mitochondrial Proteins
  • Reactive Oxygen Species
  • Recombinant Proteins
  • TUFM protein, human
  • beta Catenin
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3
  • AMP-Activated Protein Kinases
  • Peptide Elongation Factor Tu
  • Tufm protein, mouse