Co-localization of alpha1-adrenoceptors and GPR55: a novel prostate cancer paradigm?

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Patil, Kalyani Chimajirao ; McPherson, Laura ; Daly, Craig James (2015)

α1-adrenoceptors (α1-ARs) and ‘cannabinoid-like’ G Protein Coupled Receptor 55 (GPR55) belong to the G-protein coupled receptor (GPCR) family and play a crucial role in regulating prostate function. Although physical and functional interactions between the cannabinoid and adrenergic systems have been reported, analysis of functional interactions between α1-AR and GPR55 in normal and neoplastic prostate has not been reported. Since GPR55 levels are high in rodent adrenal gland, we propose a function link between the adrenergic system and GPR55 receptor. Confocal Laser Scanning Microscopy (CLSM) was employed to examine the endogenous α1-AR and GPR55 expression and their co-localization, expressed as fluorescence, in vitro in human andro-gen-insensitive PC-3 and androgen-sensitive LNCaP prostatic carcinoma cell lines, using the fluo-rescent ligands - Syto 62 (nuclear stain), BODIPY FL-Prazosin (QAPB; fluorescent quinazoline α1-AR ligand) and Tocriflour (T1117; a novel fluorescent diarylpyrazole cannabinoid/GPR55 ligand). Fluorescent ligand binding in untreated PC-3 cells and LNCaP cells and spheroids showed heterogeneous expression of both α1-ARs and GPR55. A small proportion of cells had both α1-ARs and GPR55 in relatively equal numbers indicating a degree of co-localization. Co-localization of fluorescent ligand binding exhibited a stronger correlation in LNCaP (0.87) as compared to PC-3 (0.63) cells. Upregulation of α1-AR was observed in PC-3 cells following chronic doxazosin incuba-tion. Robust T1117 binding, suggestive of GPR55 upregulation, was also observed in these cells. The presence of subtype-rich cells with a degree of co-localization between α1-ARs and GPR55 indicates a possibility for dimerisation or functional interaction and a new paradigm for functional synergism in which interactions may be either between cells or involve converging intracellular signaling processes.
  • References (36)
    36 references, page 1 of 4

    Russell, P.J. and Kingsley, E.A. (2003) Human Prostate Cancer Cell Lines. Methods in Molecular Medicine Prostate Cancer Methods and Protocols, 81, 21-39. Isaacs, J.T. (1994) The Role of Androgens in Prostatic Cancer. Vitamins & Hormones, 49, 433-502.

    Crawford, E.D., Eisenberger, M.A., McLeod, D.C., Spaulding, J., Benson, R., Dorr, F.A., Blumenstein, B.A., Davis, M.A. and Goodman, P.J. (1989) A Controlled Randomized Trial of Leuprolide with and without Flutamide in Prostatic Cancer. New England Journal of Medicine, 321, 419-424. Daaka, Y.G. (2004) Proteins in Cancer: The Prostate Cancer Paradigm. Sci STKE, 216, 1-10. Hennenberg, M., Stief, C.G. and Gratzke, C. (2014) Prostatic a1-adrenoceptors: New Concepts of Function, Regulation, and Intracellular Signaling. Neurology & Urodynamics, 33, 1074-1085. Kyprianou, N., Chon, J. and Benning, C.M. (2000) Effects of Alpha1-Adrenoceptor (α1-AR) Antagonists on Cell Proliferation and Apoptosis in the Prostate: Therapeutic Implications in Prostatic Disease. The Prostate Supplement, 9, 42-46.<42::AID-PROS9>3.0.CO;2-U

    Desiniotis, A. and Kyprianou, N. (2011) Advances in the Design and Synthesis of Prazosin Derivatives over the Last Ten Years. Expert Opinion on Therapeutic Targets, 15, 1405-1418. Gray, K., Short, J. and Ventura, S. (2008) The α1A-Adrenoceptor Gene Is Required for the α1L-Adrenoceptor-Mediated Response in Isolated Preparations of the Mouse Prostate. British Journal of Pharmacology, 155, 103-109.

    Kyprianou, N., Litvak, J., Alexander, R.B., Borkowski, A. and Jacobs, S.C. (1998) Induction of Prostate Apoptosis by Doxazosin. Journal of Urology, 159, 1810-1815.

    [10] Chon, J., Isaacs, J.T., Borkowski, A., Partin, A.W., Jacobs, S.C. and Kyprianou, N. (1999) α-1 Adrenoceptor Antagonists Terazosin and Doxazosin Induce Prostate Apoptosis without Affecting Cell Proliferation in Patients with Benign Prostatic Hyperplasia. Journal of Urology, 161, 2002-2008.

    [11] Harris, A.M., Warner, B.W., Wilson, J.M., Becker, A., Rowland, R.G., Conner, W., Lane, M., Kimbler, K., Durbin, E.B., Baron, A.T. and Kyprianou, N. (2007) Effect of α1-Adrenoceptor Antagonist Exposure on Prostate Cancer Incidence: An Observational Cohort Study. The Journal of Urology, 178, 2176-2180.

    [12] Kyprianou, N. (2003) Doxazosin and Terazosin Suppress Prostate Growth by Inducing Apoptosis: Clinical Significance. The Journal of Urology, 169, 1520-1525.

    [13] Walden, P.D., Globina, Y. and Nieder, A. (2004) Induction of Anoikis by Doxazosin in Prostate Cancer Cells Is Associated with Activation of Caspase-3 and a Reduction of Focal Adhesion Kinase. Urological Research, 32, 261-265.

    [14] Garrison, J. and Kyprianou, N. (2006) Doxazosin Induces Apoptosis of Benign and Malignant Prostate Cells via a Death Receptor-Mediated Pathway. Cancer Research, 66, 464-472.

    [15] Henstridge, C.M. (2012) Off-Target Cannabinoid Effects Mediated by GPR55. Pharmacology, 89, 179-187.

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