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Inhibition of HIF‐1 alpha and VEGF expression by the chemopreventive bioflavonoid apigenin is accompanied by Akt inhibition in human prostate carcinoma PC3‐M cells
Author(s) -
Mirzoeva Salida,
Kim Nam Deuk,
Chiu Karen,
Franzen Carrie A.,
Bergan Raymond C.,
Pelling Jill C.
Publication year - 2008
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.20421
Subject(s) - apigenin , protein kinase b , pi3k/akt/mtor pathway , cancer research , biology , hypoxia inducible factors , phosphorylation , hif1a , pharmacology , signal transduction , angiogenesis , microbiology and biotechnology , biochemistry , flavonoid , gene , antioxidant
Progression of cancer leads to hypoxic solid tumors that mount specific cell signaling responses to low oxygen conditions. An important objective of anti‐cancer therapy is the development of new drugs that suppress hypoxic responses in solid tumors. Apigenin is a natural flavone that has been shown to have chemopreventive and/or anti‐cancer properties against a number of tumor types. However, the mechanisms underlying apigenin's chemopreventive properties are not yet completely understood. In this study, we have investigated the effects of apigenin on expression of hypoxia‐inducible factor‐1 (HIF‐1) in human metastatic prostate PC3‐M cancer cells. We found that hypoxia induced a time‐dependent increase in the level of HIF‐1α subunit protein in PC3‐M cells, and treatment with apigenin markedly decreased HIF‐1α expression under both normoxic and hypoxic conditions. Further, apigenin prevented the activation of the HIF‐1 downstream target gene vascular endothelial growth factor (VEGF). We then showed that apigenin inhibited expression of HIF‐1α by reducing stability of the protein as well as by reducing the level of HIF‐1α mRNA. We also found that apigenin inhibited Akt and GSK‐3β phosphorylation in PC3‐M cells. Further experiments demonstrated that constitutively active Akt blunted the effect of apigenin on HIF‐1α expression. Taken together, our results identify apigenin as a bioflavonoid that inhibits hypoxia‐activated pathways linked to cancer progression in human prostate cancer, in particular the PI3K/Akt/GSK‐3 pathway. Further studies on the mechanism of action of apigenin will likely provide new insight into its applicability for pharmacologic targeting of HIF‐1α for cancer therapeutic or chemopreventive purposes. © 2008 Wiley‐Liss, Inc.