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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Wang, Wenxian Liu, Jinsong Wang, Junjian Gao, Minghui Wong, Chi-wai |
| Description | Author Affiliation: Gao M ( Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.) |
| Abstract | BACKGROUND AND PURPOSE: Hyperactivation of phosphatidylinositol 3-kinase (PI3K), commonly observed in cancer, is believed to promote cancer cell growth and survival. Appropriate mitochondrial function is an integral part of cellular function. How PI3K affects mitochondrial homeostasis is not fully understood. EXPERIMENTAL APPROACH: Mitochondrial mass, membrane potential and reactive oxygen species (ROS) were quantified by three different fluorogenic probes. Gene expression at the levels of mRNA and protein were measured by quantitative RT-PCR and Western analysis. KEY RESULTS: Using the PI3K inhibitors LY294002 and PI103, we found that suppressing PI3K activity altered mitochondrial function. Specifically, LY294002 and PI103 suppressed the mRNA expression levels of mitochondrial regulators nuclear respiratory factors 1 and 2 (NRF1 and NRF2). As NRF1 and NRF2 are under the transcriptional control of peroxisome proliferator-activated receptor γ coactivators-1 and -1ß (PGC-1 and PGC-1ß), we found that suppressing PI3K activity selectively reduced both the mRNA and protein levels of PGC-1ß but not PGC-1 . Reducing PGC-1ß expression also led to reduced mRNA expression levels of uncoupling protein 1, 2 (UCP1 and UCP2) and superoxide dismutase 2. Correspondingly, mitochondrial membrane potential (Δψ(m)) and ROS levels were increased. Finally, we partially blunted the LY294002-mediated growth suppression by using an antioxidant or over-expressing PGC-1ß. CONCLUSIONS AND IMPLICATIONS: PI3K regulates mitochondrial homeostasis in part through PGC-1ß and blocking this pathway induces ROS to arrest cell growth at the G1 phase. |
| ISSN | 00071188 |
| e-ISSN | 14765381 |
| Journal | British Journal of Pharmacology |
| Issue Number | 4 |
| Volume Number | 162 |
| Language | English |
| Publisher | Wiley Online Library(on behalf of The British Pharmacological Society) |
| Publisher Date | 2011-02-01 |
| Publisher Place | Great Britain (UK) |
| Access Restriction | Open |
| Subject Keyword | Carrier Proteins Metabolism Gene Expression Regulation, Neoplastic Mitochondria Phosphatidylinositol 3-Kinase Antioxidants Pharmacology Genetics Cell Line, Tumor Enzyme Inhibitors G1 Phase Drug Effects GA-Binding Protein Transcription Factor Genes, Reporter Heat-Shock Proteins Ion Channels Membrane Potential, Mitochondrial Mitochondrial Proteins Nuclear Respiratory Factor 1 Antagonists & Inhibitors Promoter Regions, Genetic RNA, Messenger RNA, Small Interfering Reactive Oxygen Species Superoxide Dismutase Transcription Factors Research Support, Non-U.S. Gov't |
| Content Type | Text |
| Resource Type | Article |
| Subject | Pharmacology |
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