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: Gambogic acid (GA) is the major active ingredient of gamboge, which has been shown to possess antitumor effect by in vitro and in vivo study.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.