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

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Abstract

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.

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Abbreviations

EMT:

Epithelial-to-mesenchymal transition

TUFM:

Tu translation elongation factor, mitochondrial

GLUT1:

Glucose transporter 1

GLUT4:

Glucose transporter 4

LDHA:

Lactate dehydrogenase A

ECAR:

Extracellular acidification rate

2-DG:

2-Deoxyglucose

AMPK:

AMP-activated protein kinase

GSK3β:

Glycogen synthase kinase 3β

ACC:

Acetyl-CoA carboxylase

AXIN2:

Axis inhibition protein 2

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

CTCs:

Circulating tumor cells

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Acknowledgments

We thank Drs. Yunneng Tang, Guangwen Shu, and other members of the laboratory for their critical comments and insightful discussions. This work was supported by the National Science Foundation of China (81472603) and the Chinese Ministry of Science and Technology (2011CB966200).

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    Authors and Affiliations

    1. State Key Laboratory of Cell Biology, Innovation Center for Cell Signalling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai, 200031, China

      Kai He, Xiaojie Guo, Yi Liu, Jingsong Li, Ying Hu, Dongmei Wang & Jianguo Song

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    Correspondence to Jianguo Song.

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    Kai He and Xiaojie Guo have contributed equally to this work.

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    He, K., Guo, X., Liu, Y. et al. TUFM downregulation induces epithelial–mesenchymal transition and invasion in lung cancer cells via a mechanism involving AMPK-GSK3β signaling. Cell. Mol. Life Sci. 73, 2105–2121 (2016). https://doi.org/10.1007/s00018-015-2122-9

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