Succinate dehydrogenase 5 (SDH5) regulates glycogen synthase kinase 3β-β-catenin-mediated lung cancer metastasis

Jun Liu; Liuwei Gao; Hua Zhang; Daowei Wang; Meng Wang; Jianquan Zhu; Cong Pang; Changli Wang

doi:10.1074/jbc.M113.450106

Succinate dehydrogenase 5 (SDH5) regulates glycogen synthase kinase 3β-β-catenin-mediated lung cancer metastasis

J Biol Chem. 2013 Oct 11;288(41):29965-73. doi: 10.1074/jbc.M113.450106. Epub 2013 Aug 27.

Authors

Jun Liu¹, Liuwei Gao, Hua Zhang, Daowei Wang, Meng Wang, Jianquan Zhu, Cong Pang, Changli Wang

Affiliation

¹ From the Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin 300060, China.

Abstract

We demonstrate that loss of succinate dehydrogenase 5 (SDH5) expression initiates epithelial-mesenchymal transition (EMT), which is visualized by the repression of E-cadherin and up-regulation of vimentin in lung cancer cell lines and clinical lung cancer specimens. In SDH5 knock-out mice, lung epithelial cells exhibited elevated mesenchymal markers, which is characteristic of EMT. Using a human lung xenograft-mouse model, we observed that knocking down endogenous SDH5 in human carcinoma cells leads to the development of multiple lymph node metastases. Moreover, our data indicate that SDH5 functions as a critical protein in regulating EMT by modulating the glycogen synthase kinase (GSK)-3β-β-catenin signaling pathway. These results reveal a critical role for SDH5 in EMT and suggest that SDH5 may be a prognostic biomarker and potential therapeutic target for lung cancer metastasis.

Keywords: Biomarkers; E-cadherin; EMT; Lung Cancer; Metastasis; Mitochondrial Protein; SDH5.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blotting, Western
Cell Line, Tumor
Cell Movement
Epithelial-Mesenchymal Transition
Glycogen Synthase Kinase 3 / genetics
Glycogen Synthase Kinase 3 / metabolism*
Glycogen Synthase Kinase 3 beta
Heterografts
Humans
Immunohistochemistry
Lung Neoplasms / genetics
Lung Neoplasms / metabolism
Lung Neoplasms / pathology*
Male
Mice
Mice, Knockout
Mice, Nude
Microscopy, Confocal
Mitochondrial Proteins / genetics
Mitochondrial Proteins / metabolism*
Neoplasm Metastasis
Protein Binding
Protein Phosphatase 2 / genetics
Protein Phosphatase 2 / metabolism
RNA Interference
Signal Transduction
Succinate Dehydrogenase / genetics
Succinate Dehydrogenase / metabolism*
Tumor Burden
beta Catenin / genetics
beta Catenin / metabolism*

Substances

Mitochondrial Proteins
SDHAF2 protein, human
beta Catenin
Succinate Dehydrogenase
GSK3B protein, human
Glycogen Synthase Kinase 3 beta
Gsk3b protein, mouse
Glycogen Synthase Kinase 3
Protein Phosphatase 2