Abstract
Abstract Insulin-like growth factor-I (IGF-I) and its receptor (IR) plays an important role in prostate cancer development and progression. IGF-I binds to the IGF-IR that transduces signals to the nucleus and mitochondria primarily via the mitogen-activated protein kinase (MAPK) and PI3K/Akt pathways facilitating increased cell survival and proliferation. Agents that are capable of inhibiting IGF-signaling pathway might be useful in the prevention and/or therapy of prostate cancer. Apigenin, a common dietary flavonoid abundantly present in fruits and vegetables has shown remarkable cancer preventive and cancer therapeutic effects. The mechanisms underlying the cancer-protective effect remains elusive. We determined the role of IGF-signaling and its downstream and other associated events by apigenin using TRAMP model. TRAMP represents males spontaneously develop prostatic adenocarcinoma that progresses through multiple stages and exhibits both histological and molecular features similar to that of human prostate cancer. TRAMP males exhibit an increase in the level of serum IGF-I, uPA and VEGF; p-Akt (Ser473), p-ERK1 (T202/Y204) and p-ERK2 (T185/Y187) in the dorso-lateral prostate of TRAMP mice in age-dependent manner, compared to non-transgenic littermates. Oral intake of apigenin at 20- and 50- microg/mouse/day (gavaged in 0.2 ml vehicle containing 0.5% methyl cellulose and 0.025% Tween 20) was provided for six days per week for 20 weeks; whereas the third group received vehicle only and served as control. Apigenin intake by TRAMP mice from 8-28 weeks of age exhibited marked reduction in tumor growth with no signs of metastasis and also resulted in a significant decrease in the wet weight of dorso-lateral and ventral lobes of the prostate and genitourinary apparatus. Apigenin intake exhibited a marked dose-dependent reduction in the levels of IGF-I along with significant increase in the levels of IGFBP-3 in the serum of TRAMP mice. The modulation of IGF-I/IGFBP3 was associated with suppression of p-ERK1 (T202/Y204) and p-ERK2 (T185/Y187) and p-Akt (Ser473) levels measured in the tissue lysates from the dorso-lateral prostates of these mice. Furthermore, apigenin intake resulted in marked inhibition of the target genes regulating angiogenesis and metastasis, notably VEGF, uPA, MMP-2 and -9 in the mouse serum. Taken together, this study provides evidence that in vivo growth inhibitory effects of apigenin involve inhibition of IGF-I signaling axis in prostate cancer and further support the development of apigenin as a promising anticancer agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4599. doi:10.1158/1538-7445.AM2011-4599
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