Gambogic acid suppresses hypoxia-induced hypoxia-inducible factor-1α/vascular endothelial growth factor expression via inhibiting phosphatidylinositol 3-kinase/Akt/mammalian target protein of rapamycin pathway in multiple myeloma cells.
Bottom Line: We found that hypoxia induced increase in the level of HIF-1α subunit protein and activated the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target protein of rapamycin (mTOR) pathway.Mechanistic studies exhibited that GA inhibited the production of HIF-1α by reducing phosphorylation of Akt and mTOR in U266 cells.Taken together, our results identify that GA suppresses hypoxia-activated pathways that are linked to MM progression, at least partly, by the inhibition of the PI3K/Akt/mTOR signaling pathway.
Affiliation: Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Medical School, Zhongda Hospital, Southeast University, Nanjing, China.Show MeSH
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Mentions: The PI3K/Akt/mTOR pathway is a crucial regulator of cell proliferation and angiogenesis. It has been reported that PI3K/Akt signaling pathway may be involved in hypoxia-induced HIF-1α protein accumulation and its downstream target gene expression.(14,15) To explore whether GA can inhibit hypoxia-mediated activation of PI3K/Akt/mTOR, U266 cells were treated with 0.2 μM GA for 4 h under hypoxia. Our data showed hypoxia augmented phosphorylation of Akt and mTOR in U266 cells, which were all attenuated by GA (Fig. 4a,b). Interestingly, GA did not affect the total protein levels of these kinases, suggesting that the action of GA was specific to the protein activation.
Affiliation: Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Medical School, Zhongda Hospital, Southeast University, Nanjing, China.