Caveolae Contribute to the Apoptosis Resistance Induced by the α1A-Adrenoceptor in Androgen-Independent Prostate Cancer Cells

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.

The Caveolin-1 Connection to Cell Death and Survival

“…Additionally, in human prostate cancer cells, Caveolin-1 presence favors phenylephrine-induced resistance to thapsigargin mediated cell death. This Caveolin-1-dependent effect is characterized by reduced caspase-3 activation and PARP cleavage in a Bax dependent fashion [140]. In addition, in renal cancer cells, Caveolin-1 is up-regulated after chronic treatment with doxorubicin.…”

Phosphatidylserine dictates the assembly and dynamics of caveolae in the plasma membrane

“…This up-regulation could be quite problematic as Cav1 is thought to promote the dissemination of cancer via metastatic migration through the lymphatic system and to protect cells from apoptosis (59). Although a previous study has demonstrated that caveolae can provide resistance to apoptosis in androgen-independent prostate cancer cells (60), the biological signals associated with non-caveolar Cav1 are incompletely understood. In this regard, non-caveolar Cav1 has been shown to influence the expression of important mediators of metastasis and lymphangiogenesis such as matrix metalloprotease 9 and vascular endothelial growth factor, respectively PtdSer is required for caveolae (59,61).…”

Age-related changes in the innervation of the prostate gland

“…However, there are inconsistencies between the sequencing data and functional studies on α 1A -adrenoceptors and muscarinic receptors. Two papers have suggested a role for the α 1A -adrenoceptor in proliferation of LNCaP cells 149 and chemoresistance of DU145 cells; 150 however receptor detection was based on α 1A -drenoceptors antibodies, which are notorious for lack of specificity 151 . The muscarinic receptor agonist carbachol likewise stimulates proliferation of LNCaP cells despite an apparent lack of mRNA for any of the relevant acetylcholine receptor subtypes 135 …”