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: To investigate why GA exhibited more marked effect on VEGF secretion and expression of U266 cells under hypoxia, real time-PCR, western blots and immunofluorescence were used to evaluate the expression of HIF-1α, the key regulator of hypoxia. The results showed that in both of normoxia and hypoxia, the levels of HIF-1α mRNA were unchanged with or without GA treatment on U266 cells (Fig. 3a), but compared with little expression under normoxia, hypoxic condition elicited a robust increase of HIF-1α protein level, which can be reduced by GA in a concentration-dependent manner (Fig. 3b,c). This observation was confirmed by an immunofluorescence assay in vitro that the intracellular expression of HIF-1α was relatively sparser and weaker compared to those before GA treatment (Fig. 3d). Taken together, these findings suggested that GA might downregulate HIF-1α through decreasing translation.
Affiliation: Department of Hematology and Oncology (Key Department of Jiangsu Medicine), Medical School, Zhongda Hospital, Southeast University, Nanjing, China.