Remember Me
Or use your Academic/Social account:


Or use your Academic/Social account:


You have just completed your registration at OpenAire.

Before you can login to the site, you will need to activate your account. An e-mail will be sent to you with the proper instructions.


Please note that this site is currently undergoing Beta testing.
Any new content you create is not guaranteed to be present to the final version of the site upon release.

Thank you for your patience,
OpenAire Dev Team.

Close This Message


Verify Password:
Verify E-mail:
*All Fields Are Required.
Please Verify You Are Human:
fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Patil, Kalyani Chimajirao; McPherson, Laura; Daly, Craig James (2015)
Publisher: Scientific Publishing
Languages: English
Types: Article
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.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 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. http://dx.doi.org/10.1385/1-59259-372-0:21 Isaacs, J.T. (1994) The Role of Androgens in Prostatic Cancer. Vitamins & Hormones, 49, 433-502. http://dx.doi.org/10.1016/S0083-6729(08)61152-8
    • 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. http://dx.doi.org/10.1056/NEJM198908173210702 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. http://dx.doi.org/10.1002/nau.22467 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. http://dx.doi.org/10.1002/1097-0045(2000)45:9+<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. http://dx.doi.org/10.1517/14728222.2011.641534 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. http://dx.doi.org/10.1038/bjp.2008.245
    • 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. http://dx.doi.org/10.1016/S0022-5347(01)63162-8
    • [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. http://dx.doi.org/10.1016/S0022-5347(05)68873-8
    • [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. http://dx.doi.org/10.1016/j.juro.2007.06.043
    • [12] Kyprianou, N. (2003) Doxazosin and Terazosin Suppress Prostate Growth by Inducing Apoptosis: Clinical Significance. The Journal of Urology, 169, 1520-1525. http://dx.doi.org/10.1097/01.ju.0000033280.29453.72
    • [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. http://dx.doi.org/10.1007/s00240-003-0365-7
    • [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. http://dx.doi.org/10.1158/0008-5472.CAN-05-2039
    • [15] Henstridge, C.M. (2012) Off-Target Cannabinoid Effects Mediated by GPR55. Pharmacology, 89, 179-187. http://dx.doi.org/10.1159/000336872
    • [16] Chung, S.C., Hammarsten, P., Josefsson, A., Stattin, P., Granfors, T. and Egevad, L. (2009) A High Cannabinoid CB1 Receptor Immune-Reactivity Is Associated with Disease Severity and Outcome in Prostate Cancer. European Journal of Cancer, 45, 174-182. http://dx.doi.org/10.1016/j.ejca.2008.10.010
    • [17] Melck, D., Rueda, D., Galve-Roperh, I., De Petrocellis, L., Guzmán, M. and Di Marzo, V. (1999) Involvement of the cAMP/Protein Kinase A Pathway and of Mitogen-Activated Protein Kinase in the Anti-Proliferative Effects of Anandamide in Human Breast Cancer Cells. FEBS Letters, 463, 235-240. http://dx.doi.org/10.1016/S0014-5793(99)01639-7
    • [18] Sánchez, M.G., Ruiz-Llorente, L., Sánchez, A.M. and Díaz-Laviada, I. (2003) Activation of Phosphoinositide 3-Kinase/PKB Pathway by CB1 and CB2 Cannabinoid Receptors Expressed in Prostate PC-3 Cells: Involvement in Raf-1 Stimulation and NGF Induction. Cellular Signalling, 15, 851-859. http://dx.doi.org/10.1016/S0898-6568(03)00036-6
    • [19] Nithipatikom, K., Endsley, M.P., Isbell, M.A., Falck, J.R., Iwamoto, Y., Hillard, C.J. and Campbell, W. (2004) 2-Arachidonoylglycerol: A Novel Inhibitor of Androgen-Independent Prostate Cancer Cell Invasion. Cancer Research, 64, 8826-8830. http://dx.doi.org/10.1158/0008-5472.CAN-04-3136
    • [20] Sarfaraz, S., Afaq, F., Adhami, V.M. and Mukhtar, H. (2005) Cannabinoid Receptor as a Novel Target for the Treatment of Prostate Cancer. Cancer Research, 65, 1635-1641. http://dx.doi.org/10.1158/0008-5472.CAN-04-3410
    • [21] Brown, I., Cascio, M.G., Wahle, K.W., Smoum, R., Mechoulam, R. and Ross, R.A. (2010) Cannabinoid Receptor-Dependent and -Independent Anti-Proliferative Effects of Omega-3 Ethanolamides in Androgen Receptor-Positive and -Negative Prostate Cancer Cell Lines. Carcinogenesis, 31, 1584-1591. http://dx.doi.org/10.1093/carcin/bgq151
    • [22] Andradas, C., Caffarel, M.M., Perez-Gomez, E., Salazar, M., Lorente, M., Velasco, G., Guzman, M. and Sanchez, M. (2011) The Orphan G Protein-Coupled Receptor GPR55 Promotes Cancer Cell Proliferation via ERK. Oncogene, 30, 245-252. http://dx.doi.org/10.1038/onc.2010.402
    • [23] Bondarenko, A., Waldeck-Weiermair, M., Naghdi, S., Poteser, M., Malli, R. and Graier, W. (2010) GPR55-Dependent and -Independent Ion Signaling in Response to Lysophosphatidylinositol in Endothelial Cells. British Journal of Pharmacology, 161, 308-320. http://dx.doi.org/10.1111/j.1476-5381.2010.00744.x
    • [24] Daly, C.J., Ross, R.A., Whyte, J., Henstridge, C.M., Irving, A.J. and McGrath, J.C. (2010) Fluorescent Ligand Binding Reveals Heterogeneous Distribution of Adrenoceptors and “Cannabinoid-Like” Receptors in Small Arteries. British Journal of Pharmacology, 159, 787-796. http://dx.doi.org/10.1111/j.1476-5381.2009.00608.x
    • [25] Daly, C.J., Milligan, C.M., Milligan, G., Mackenzie, J.F. and Mcgrath, J.C. (1998) Cellular Localization and Pharmacological Characterization of Functioning Alpha-1 Adrenoceptors by Fluorescent Ligand Binding and Image Analysis Reveals Identical Binding Properties of Clustered and Diffuse Populations of Receptors. The Journal of Pharmacology and Experimental Therapeutics, 286, 984-990.
    • [26] Hudson, B.D., Hébert, T.E. and Kelly, M. (2010) Physical and Functional Interactions between CB1 Cannabinoid Receptors and β2-Adrenocepors. British Journal of Pharmacology, 160, 627-642. http://dx.doi.org/10.1111/j.1476-5381.2010.00681.x
    • [27] Daly, C.J. and McGrath, J.C. (2011) Previously Unsuspected Widespread Cellular and Tissue Distribution of Beta-Adrenoceptors and Its Relevance to Drug Action. Trends in Pharmacological Sciences, 32, 219-226. http://dx.doi.org/10.1016/j.tips.2011.02.008
    • [28] Angers, S., Salapour, A. and Bouvier, M. (2002) Dimerization: An Emerging Concept for G Protein-Coupled Receptor Ontogeny and Function. Annual Review of Pharmacology and Toxicology, 42, 409-435. http://dx.doi.org/10.1146/annurev.pharmtox.42.091701.082314
    • [29] Milligan, G., Pediani, J., Fidock, M. and López-Giménez, J.F. (2004) Dimerization of Alpha1-Adrenoceptors. Biochemical Society Transactions, 32, 847-850.
    • [30] Uberti, M., Hague, C., Oller, H., Minneman, K. and Hall, R. (2005) Heterodimerisation with β2-Adrenergic Receptors Promotes Surface Expression and Functional Activity of α1D-Adrenergic Receptors. Journal of Pharmacology and Experimental Therapeutics, 313, 16-23. http://dx.doi.org/10.1124/jpet.104.079541
    • [31] Copik, A.J., Ma, C., Kosaka, A., Sahdeo, S., Trane, A., Ho, H., Dietrich, P.S., Yu, H., Ford, A.P., Button, D. and Milla, M.E. (2009) Facilitatory Interplay in α1a and β2 Adrenoceptor Function Reveals a Non-Gq Signaling Mode: Implications for Diversification of Intracellular Signal Transduction. Molecular Pharmacology, 75, 713-728. http://dx.doi.org/10.1124/mol.108.050765
    • [32] Pennefather, J.N., Lau, W.A., Mitchelson, F. and Ventura, S. (2000) The Autonomic and Sensory Innervation of the Smooth Muscle of the Prostate Gland: A Review of Pharmacological and Histological Studies. Journal of Autonomic Pharmacology, 20, 193-206. http://dx.doi.org/10.1046/j.1365-2680.2000.00195.x
    • [33] Aarons, R.D., Nies, A.S., Gal, J., Hegstrand, L.R. and Molinoff, P.B. (1980) Elevation of Beta-Adrenergic Receptor Density in Human Lymphocytes after Propranolol Administration. Journal of Clinical Investigation, 65, 949-957. http://dx.doi.org/10.1172/JCI109781
    • [34] Foster Jr., H.E., Yono, M., Shin, D., Takahashi, W., Pouresmail, M., Afiatpour, P. and Latifpour, J. (2004) Effects of Chronic Administration of Doxazosin on α1-Adrenoceptors in the Rat Prostate. The Journal of Urology, 172, 2465- 2470. http://dx.doi.org/10.1097/01.ju.0000138475.89790.88
    • [35] Yono, M., Poster Jr., H.E., Shin, D., Takahashi, W., Pouresmail, M. and Latifpour, J. (2004) Doxazosin Treatment Causes Differential Alterations of α1-Adrenoceptor Subtypes in the Rat Kidney, Heart and Aorta. Life Sciences, 75, 2605-2614. http://dx.doi.org/10.1016/j.lfs.2004.08.001
    • [36] Kreda, S.M., Sumner, M., Fillo, S., Ribeiro, C.M., Luo, G.X., Xie, W., Daniel, K.W., Shears, S., Collins, S. and Wetsel, W.C. (2001) α1-Adrenergic Receptors Mediate LH-Releasing Hormone Secretion through Phospholipases C and A2 in Immortalized Hypothalamic Neurons. Endocrinology, 142, 4839-4851.
    • [37] Schlicker, E., Timm, J., Zentner, J. and Gothert, M. (1997) Cannabinoid CB1 Receptor-Mediated Inhibition of Noradrenaline Release in the Human and Guinea-Pig Hippocampus. Naunyn-Schmiedeberg's Archives of Pharmacology, 356, 583-589. http://dx.doi.org/10.1007/PL00005093
    • [38] Schultheiss, T., Flau, K., Kathmann, M., Gothert, M. and Schlicker, E. (2005) Cannabinoid CB1 Receptor-Mediated Inhibition of Noradrenaline Release in Guinea-Pig Vessels, but Not in Rat and Mouse Aorta. Naunyn-Schmiedeberg's Archives of Pharmacology, 372, 139-146. http://dx.doi.org/10.1007/s00210-005-0007-4
    • [39] Pakdeechote, P., Dunn, W.R. and Ralevic, V. (2007) Cannabinoids Inhibit Noradrenergic and Purinergic Sympathetic Cotransmission in the Rat Isolated Mesenteric Arterial Bed. British Journal of Pharmacology, 152, 725-733. http://dx.doi.org/10.1038/sj.bjp.0707397
    • [40] Tam, J., Trembovler, V., Di Marzo, V., Petrosino, S., Leo, G., Alexandrovich, A., Regev, E., Casap, N., Shteyer, A., Ledent, C., Karsak, M., Zimmer, A., Mechoulam, R., Yirmiya, R., Shohami, E. and Bab, I. (2008) The Cannabinoid CB1 Receptor Regulates Bone Formation by Modulating Adrenergic Signaling. The FASEB Journal, 22, 285-294. http://dx.doi.org/10.1096/fj.06-7957com
    • [41] Pineiro, R., Maffucci, T. and Falasca, M. (2011) The Putative Cannabinoid Receptor GPR55 Defines a Novel Autocrine Loop in Cancer Cell Proliferation. Oncogene, 30, 142-152. http://dx.doi.org/10.1038/onc.2010.417
  • No related research data.
  • No similar publications.

Share - Bookmark

Cite this article