Abstract 5229: Apigenin inhibits TGF-beta-induced VEGF expression in human prostate carcinoma cells via Smad2/3 and Src/FAK/Akt signaling pathways

Abstract

Abstract Prostate cancer mortality is primarily attributed to development of metastases rather than primary, organ-confined disease. Solid tumors, such as prostate carcinomas, rely on establishment of vascular supply and angiogenesis for their growth and metastasis. Vascular endothelial growth factor (VEGF) is a key regulator of blood supply establishment in prostate tissue. VEGF production is regulated by two major mechanisms, hypoxia (low oxygen supply) and various cytokines. Interplay between hypoxia, cytokines, growth factors and angiogenic factors determines development and progression of cancer. In our previous studies, we demonstrated that the chemopreventive bioflavonoid apigenin (4α, 5, 7-trihydroxyflavone) inhibited hypoxia-induced elevation of VEGF production in prostate cancer cells at low oxygen conditions characteristic for solid tumors. Low oxygen (hypoxia) and transforming growth factor-β are two major factors responsible for increased VEGF secretion in prostate cancer. In metastatic prostate cancer, TGF-β serves as a promoter of prostate tumorigenesis. Activation of TGF-β receptors induces phosphorylation of its cytoplasmic effectors, receptor-regulated Sma- and Mad-related proteins (Smads). Phosphorylated Smads translocate to the nucleus and bind to DNA to regulate transcription of specific genes, notably VEGF. Blocking of TGF-β action inhibits tumor viability, tumor cell migration and metastasis in prostate cancer. Therefore, reduction of TGF-β production and activity may be a promising target for controlling tumor growth and ultimately prostate cancer metastasis. In the present studies, we investigated the inhibitory effect of apigenin on TGF-β-induced VEGF production and the mechanisms underlying this action. We found that VEGF expression was induced by TGF- β1 in highly metastatic human prostate cancer PC3-M and LNCaP C4-2B cells, and treatment with apigenin markedly decreased VEGF production. Furthermore, apigenin inhibited TGF-β1-induced phosphorylation and nuclear translocation of Smad2 and Smad3. We also found that apigenin inhibited Src, FAK and Akt phosphorylation in PC3-M and LNCaP C4-2B cells. Further experiments demonstrated that constitutively active Src reversed the inhibitory effect of apigenin on VEGF expression and Smad2/3 phosphorylation. Taken together, our results suggest that apigenin inhibits prostate carcinogenesis by modulating TGF-β-activated pathways linked to cancer progression and metastases, in particular the Smad2/3 and Src/FAK/Akt pathways. These findings provide new insights into molecular pathways targeted by apigenin, and reveal a novel molecular mechanism underlying the antiangiogenic potential of apigenin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5229. doi:1538-7445.AM2012-5229