Overall goal of the grant is to conduct in depth studies to identify and develop molecular-mechanism based intervention approach for human prostate cancer (PCA) by a dietary agent phytic acid. Aberrant expression of epidermal growth factor receptor family members (erbB) is shown with high frequency in prostatic intraepithelial neoplasia and invasive human PCA suggesting their role in the causation of this disease. In addition to receptor activation, ligand binding also results in a rapid disappearance of receptor from cell surface via endocytosis by promoting receptor clustering into clathrin- coated pits on membrane followed by receptor internalization. A main structural component of coated pits is clathrin lattice anchored to membrane by associated protein adaptors (Aps). AP2 is the most ubiquitous of associated proteins that specifically interact with erbB receptors. In addition to receptor, the other step is fluid-phase endocytosis mediated via P13K-AKT-Rab5 pathway. Based on high association between receptor endocytosis and mitogenic and anti-apoptotic responses, we hypothesize that impairment of both receptor-mediated and fluid-phase endocytosis, and the mitogenic and anti-apoptotic signaling associated with them is an obligatory step in the inhibition/retardation of PCA growth. In support of this hypothesis, we observed that endocytosis is operational in human PCA cells, and that a dietary agent phytic acid impairs endocytosis and mitogenic responses associated with it. Together, efforts are directed in this grant to impair receptor endocytosis signaling leading to inhibition of both mitogenic and anti-apoptotic responses as a novel and innovative strategy for the intervention of PCA by phytic acid. Using PCA cells, we will assess the inhibitory effect of phytic acid on 1) ligand-induced erbB receptor endocytosis signaling, and define the involvement of AP2 and P13K-AKT-Rab5 pathways in this process; and 2) MAPK-mediated growth and P13K-AKT-BAD- mediated anti-apoptotic pathways in response to impairment of receptor endocytosis signaling. Next, we will assess the biological significance of phytic acid on growth inhibition and/or apoptotic death of human PCA cells using both in vitro and in vivo systems, and define the involvement of molecular events identified above. The outcome of these studies will build a base for future long term studies to a) further define the role of receptor endocytosis signaling and associated events in human PCA as molecular target(s) for intervention, and b) evaluate the effect of phytic acid against PCA in investigative clinical trials with correlative laboratory studies.

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National Cancer Institute (NCI)
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Metabolic Pathology Study Section (MEP)
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Amc Cancer Research Center
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Singh, Rana P; Agarwal, Rajesh (2005) Prostate cancer and inositol hexaphosphate: efficacy and mechanisms. Anticancer Res 25:2891-903
Singh, Rana P; Agarwal, Rajesh (2004) Prostate cancer prevention by silibinin. Curr Cancer Drug Targets 4:1-11
Singh, Rana P; Tyagi, Anil K; Dhanalakshmi, Sivanandhan et al. (2004) Grape seed extract inhibits advanced human prostate tumor growth and angiogenesis and upregulates insulin-like growth factor binding protein-3. Int J Cancer 108:733-40
Singh, Rana P; Sharma, Girish; Mallikarjuna, G U et al. (2004) In vivo suppression of hormone-refractory prostate cancer growth by inositol hexaphosphate: induction of insulin-like growth factor binding protein-3 and inhibition of vascular endothelial growth factor. Clin Cancer Res 10:244-50
Agarwal, Chapla; Dhanalakshmi, Sivanandhan; Singh, Rana P et al. (2004) Inositol hexaphosphate inhibits growth and induces G1 arrest and apoptotic death of androgen-dependent human prostate carcinoma LNCaP cells. Neoplasia 6:646-59
Sharma, Girish; Singh, Rana P; Agarwal, Rajesh (2003) Growth inhibitory and apoptotic effects of inositol hexaphosphate in transgenic adenocarcinoma of mouse prostate (TRAMP-C1) cells. Int J Oncol 23:1413-8
Singh, Rana P; Agarwal, Chapla; Agarwal, Rajesh (2003) Inositol hexaphosphate inhibits growth, and induces G1 arrest and apoptotic death of prostate carcinoma DU145 cells: modulation of CDKI-CDK-cyclin and pRb-related protein-E2F complexes. Carcinogenesis 24:555-63
Singh, Rana P; Agarwal, Rajesh (2003) Tumor angiogenesis: a potential target in cancer control by phytochemicals. Curr Cancer Drug Targets 3:205-17
Agarwal, Chapla; Dhanalakshmi, Sivanandhan; Singh, Rana P et al. (2003) Inositol hexaphosphate inhibits constitutive activation of NF- kappa B in androgen-independent human prostate carcinoma DU145 cells. Anticancer Res 23:3855-61
Singh, Rana P; Sharma, Girish; Dhanalakshmi, Sivanandhan et al. (2003) Suppression of advanced human prostate tumor growth in athymic mice by silibinin feeding is associated with reduced cell proliferation, increased apoptosis, and inhibition of angiogenesis. Cancer Epidemiol Biomarkers Prev 12:933-9

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