Guanosine phosphate binding protein coupled receptors in prostate cancer: A review

Purpose: Androgens are the primary growth promoters of the prostate gland and yet prostate tumors progress despite androgen ablation. This progression suggests a role for additional cellular factors in the progression to androgen independent disease. We examined the role of a family of extracellular signal regulators, namely the guanosine phosphate binding (G) protein coupled receptor (GPCR) family, in prostate cancer. Materials and Methods: A comprehensive review of the literature was performed on GPCRs and prostate cancer, and supplemented with published and unpublished observations made at our laboratory. Emphasis was placed on the mechanistic aspects of mitogenic signaling pathways involved to identify potential targets for therapy. Results: Expression of some GPCRs and GPCR ligands is elevated in prostate cancer cells and adjacent prostatic stromal tissue. In vitro studies demonstrate that activation of GPCRs confers a distinct growth and survival advantage on prostate cancer cells, including enhanced proliferation and decreased programmed cell death (apoptosis). Specifically stimulation of GPCRs for lysophosphatidic acid and bradykinin induces proliferation of androgen independent prostate cancer cells via the activation of the extracellular signal regulated kinase (ERK) pathway. Induction of ERK by the bradykinin and lysophosphatidic acid in prostate cells proceeds via distinct pathways and involves Gαq and Gβγ subunits, respectively. The Gβγ dependent activation of ERK requires tyrosine kinases, including epidermal growth factor receptor and c-Src. Furthermore, stimulation with LPA enhances the survival of prostate cancer cells via activation of the inducible transcription factor nuclear factor-κB. Conclusions: GPCR stimulation induces proliferation and prevents apoptosis of hormone independent prostate cancer cells, indicating their important role in the progression of prostate cancer. While further confirmatory studies are required to verify the role of GPCRs in disease progression, the therapeutic implications of these studies may enhance the armamentarium in the fight against prostate cancer.