Dissecting The In vivo Role Of G Proteins In Prostate Cancer: Major clinical limitations in the treatment of advanced prostate cancer is transition of the prostate tumor to androgen-independent state, where androgen ablation therapy becomes ineffective. Factors involved in the transition of the prostate cancer to androgen-independence are not clearly defined, although peptide growth factors, which act upon their cognate receptor tyrosine kinases, have been implicated. Recent research advances demonstrate that transition of the cancer to androgen-independent state is associated with increased expression of some G protein-coupled receptors and/or their ligands. In vitro, both lipid and peptide growth factors stimulate prostate cell growth via dissociated heterotrimeric G proteins alpha(G-alpha) and/or beta gamma (G-beta gamma) subunits in response to stimulation of their associated G protein-coupled receptors. In particular, two subfamilies of G proteins (Gq and Gi) appear to play critical roles in the pathological growth of prostate cells. Specific peptide inhibitors of Gq (G-alpha-qct) and G-beta gamma (GRK2ct) signaling have recently been developed and may represent a novel therapeutic opportunity for the successful treatment of prostate cancer. The central hypothesis of this proposal is that G proteins are critical regulators of pathological growth of prostate cancer and that the targeted inhibition of Gq and G-beta gamma signaling will limit tumorigenic growth of the prostate. Both in vitro and in vivo model systems, including a mouse xenograft model, are available and will be used to test this hypothesis. To express G-alpha-qct and GRK2ct peptides in prostate cancer cells in culture and in vivo, we will utilize adenoviral vectors.
The specific aims are: (1) To determine the specific role of Gq and G-beta gamma (by using G-alpha-qct and GRK2ct) in ERK activation and prostate cell growth and migration using in vitro model systems; ( 2) To determine the molecular mechanisms by which G-alpha-q and G-beta,gamma subunits crosstalk to epidermal growth factor receptor in prostate cancer cells; and ( 3) To determine the role of Gq and G-beta gamma subunits in the in vivo growth of prostate tumors using animal model systems. The successful conclusion of these studies may identify G-alpha-qct and/or GRK2ct as novel molecular gene therapy modalities effective for the treatment of prostate cancer.
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