期刊
ONCOGENE
卷 29, 期 27, 页码 3964-3976出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2010.146
关键词
PNC1; IGF-I; mitochondria; ROS; EMT in cancer; metabolism
资金
- Science Foundation Ireland
- Health Research Board
The insulin-like growth factor (IGF-I) signalling pathway is essential for metabolism, cell growth and survival. It induces expression of the mitochondrial pyrimidine nucleotide carrier 1 (PNC1) in transformed cells, but the consequences of this for cell phenotype are unknown. Here we show that PNC1 is necessary to maintain mitochondrial function by controlling mitochondrial DNA replication and the ratio of transcription of mitochondrial genes relative to nuclear genes. PNC1 suppression causes reduced oxidative phosphorylation and leakage of reactive oxygen species (ROS), which activates the AMPK-PGC1 alpha signalling pathway and promotes mitochondrial biogenesis. Overexpression of PNC1 suppresses mitochondrial biogenesis. Suppression of PNC1 causes a profound ROS-dependent epithelial-mesenchymal transition (EMT), whereas overexpression of PNC1 suppresses both basal EMT and induction of EMT by TGF-beta. Overall, our findings indicate that PNC1 is essential for mitochondria maintenance and suggest that its induction by IGF-I facilitates cell growth whereas protecting cells from an ROS-promoted differentiation programme that arises from mitochondrial dysfunction. Oncogene (2010) 29, 3964-3976; doi:10.1038/onc.2010.146; published online 10 May 2010
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