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Guanosine phosphate binding protein coupled receptors in prostate cancer: a review
Ganesh V Raj1, Liza Barki-Harrington, Pao F Kue
1Departments of Surgery and Pharmacology-Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
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comprehensive review of the literature was performed on GPCRs and prostate cancer, and supplemented with published and unpublished observations made at our laboratory.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 Galphaq and Gbetagamma subunits, respectively. The Gbetagamma 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-kappaB.
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.
Insights
Guiding prostate cancer progression, G protein-coupled receptors (GPCRs) promote cell growth and survival. Targeting GPCRs may offer new therapeutic strategies for hormone-independent prostate tumors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Androgens are key prostate growth promoters, yet tumors can progress despite androgen ablation.
- This progression implies other cellular factors drive androgen-independent disease.
Purpose of the Study:
- To investigate the role of G protein-coupled receptors (GPCRs) in prostate cancer progression.
- To explore GPCRs as potential therapeutic targets for advanced prostate cancer.
Main Methods:
- Comprehensive literature review on GPCRs and prostate cancer.
- Analysis of in vitro data on GPCR signaling pathways.
- Focus on mitogenic signaling pathways for therapeutic target identification.
Main Results:
- Elevated expression of certain GPCRs and ligands in prostate cancer tissues.
- GPCR activation enhances prostate cancer cell proliferation and survival (inhibits apoptosis).
- Lysophosphatidic acid and bradykinin activate extracellular signal-regulated kinase (ERK) pathway in androgen-independent cells via distinct mechanisms.
Conclusions:
- GPCR stimulation drives proliferation and inhibits apoptosis in hormone-independent prostate cancer cells.
- GPCRs play a significant role in prostate cancer progression.
- Targeting GPCRs presents potential therapeutic avenues for prostate cancer treatment.