Adiponectin signals in prostate cancer cells through Akt to activate the mammalian target of rapamycin pathway.
Adiponectin has received much attention due to its beneficial effects on insulin sensitivity, and epidemiologic studies have further shown an inverse association between adiponectin levels and risk for multiple tumors, which is independent of the IGF system or other risk factors. Previous studies have shown that adiponectin can activate AMP-activated protein kinase (AMPK) in myocytes, hepatocytes, and adipocytes, suggesting that adiponectin may suppress tumor development through AMPK activation and subsequent inhibition of mammalian target of rapamycin (mTOR). However, the mechanisms through which adiponectin affects cancer cells are not understood, and it remains to be determined whether adiponectin is linked to the same downstream targets in all cells types, and in particular in cancer cells. In the present study, we demonstrate that while adiponectin stimulates AMPK in phosphatase and tensin homolog deleted on chromosome ten (PTEN) deficient LNCaP prostate cancer cells, it also increases mTOR activity as assessed by phosphorylation of two downstream targets, p70 S6 kinase and ribosomal protein S6. This adiponectin stimulation of mTOR was mediated through phosphatidylinositol 3-kinase (PI3 kinase) and Akt activation. These results show that adiponectin can activate both AMPK and PI3 kinase/Akt pathways, and that cell type-specific factors such as PTEN status may determine which of these pathways will have the dominant effect on mTOR. Therefore, while it is possible that high endogenous adiponectin levels could be protective against cancer by direct mechanisms or indirect systemic mechanisms, our results indicate that adiponectin may also directly stimulate signaling pathways that enhance the growth of some tumors.
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Division of Endocrinology, Diabetes and Metabolism Biology Program, Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
Neuwirth
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Mantzoros
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Balk
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D000263:Adenylate Kinase / Q000378:metabolism; D052242:Adiponectin / Q000502:physiology*; D004789:Enzyme Activation; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000503:physiopathology*; D011494:Protein Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D052242:Adiponectin; D011494:Protein Kinases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase