Abstract
BackgroundDuring androgen ablation prostate cancer cells' growth and survival become independent of normal regulatory mechanisms. These androgen-independent cells acquire the remarkable ability to adapt to the surrounding microenvironment whose factors, such as neurotransmitters, influence their survival. Although findings are becoming evident about the expression of α1A-adrenoceptors in prostate cancer epithelial cells, their exact functional role in androgen-independent cells has yet to be established. Previous work has demonstrated that membrane lipid rafts associated with key signalling proteins mediate growth and survival signalling pathways in prostate cancer cells.Methodology/Principal FindingsIn order to analyze the membrane topology of the α1A-adrenoceptor we explored its presence by a biochemical approach in purified detergent resistant membrane fractions of the androgen-independent prostate cancer cell line DU145. Electron microscopy observations demonstrated the colocalisation of the α1A-adrenoceptor with caveolin-1, the major protein component of caveolae. In addition, we showed that agonist stimulation of the α1A-adrenoceptor induced resistance to thapsigargin-induced apoptosis and that caveolin-1 was necessary for this process. Further, immunohistofluorescence revealed the relation between high levels of α1A-adrenoceptor and caveolin-1 expression with advanced stage prostate cancer. We also show by immunoblotting that the TG-induced apoptosis resistance described in DU145 cells is mediated by extracellular signal-regulated kinases (ERK).Conclusions/SignificanceIn conclusion, we propose that α1A-adrenoceptor stimulation in androgen-independent prostate cancer cells via caveolae constitutes one of the mechanisms contributing to their protection from TG-induced apoptosis.
Highlights
Prostate cancer is one of the most common forms of cancer in men and the second cause of cancer death in industrialized countries [1]
Conclusions/Significance: In conclusion, we propose that a1A-adrenoceptor stimulation in androgen-independent prostate cancer cells via caveolae constitutes one of the mechanisms contributing to their protection from TG-induced apoptosis
We describe the effect of PHE in the apoptosis resistance of these cells through activation of extracellular signal-regulated kinases (ERK) and our results strongly imply the involvement of caveolae in this signalling pathway
Summary
Prostate cancer is one of the most common forms of cancer in men and the second cause of cancer death in industrialized countries [1] Various factors such as androgens and growth factors regulate epithelial cell proliferation and apoptosis in the normal prostate and early-stage prostate cancer (PCa). PCa cells’ proliferation and survival often become independent of regulatory mechanisms leading to a hormone-refractory disease [2] for which there is currently no successful therapy. During androgen ablation prostate cancer cells’ growth and survival become independent of normal regulatory mechanisms. These androgen-independent cells acquire the remarkable ability to adapt to the surrounding microenvironment whose factors, such as neurotransmitters, influence their survival. Previous work has demonstrated that membrane lipid rafts associated with key signalling proteins mediate growth and survival signalling pathways in prostate cancer cells
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