g protein coupled receptors (gpcrs) and cancer

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Author: dayananda-salam

Post on 14-Jun-2015



Health & Medicine

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2. ABBREVIATIONS USED GROGrowth-regulated oncogene GAPGTPase Activating ProteinsPAR1Protease-activated receptor 1NSAI DNon-steroidal anti-inflammatory drugsSDF1Stromal Cell Derived Factor 1ERKExtracellular Receptor KinaseGEFsGuanine nucleotide exchange factorGRPGastrin Releasing PeptideCavcaveolin-1GnR HGonadotropin Releasing hormoneGRKGPCR kinaseCox2Cyclo-oxygenase 2GSK3 BGlycogen Synthase Kinase 3 BARAAndrogen Receptor ActivatorGrb2SOSGrowth factor receptor-bound protein 2- Son of SevenlessCdc4 2Cell Division Control protein homolog 42PLC-BPhospholipase C beta 3. CONTENTS1.Introduction 2.Classical GPCR Signalling 3.G proteins 4.GPCR and its Ligands 5.GPCRs in Prostate Cancer 6.Orphan GPCRs 7.References 4. INTRODUCTION GPCR-G-Protein Coupled Receptor Gatekeepers More than 900 genes, 1% of the total human genome Signals- light, hormones, neurotransmitters, peptides etc. Functions- Fight-or-flight response, taste, smell, immune system, growth etc Structure: 7 transmembrane alpha helices (7TMP) Target of 50% of all drugs worldwide 5. GPCR AND CANCER Cancer TypeReceptorLigandProcessBreast CancerPAR1ThrombinGrowth, MetastasisEP2, EP4PGE2Growth MetastasisLPA1LPAGrowthPARThrombinGrowth, MigrationEP receptorsPGE2Growth MetastasisCXCR4SDF1Migration metastasis AngiogenesisLPA1-LPA3LPAGrowth metastasisCXCR2GROGrowth angiogenesisEtaEndothelinGrowth SurvivalAT1Angiotensin IIGrowthLPA1LPAGrowth InvasionHead and Neck Cancer Non-small-cell lung cancerOvarian Cancer Prostate Cancer 6. BASIC GPCR SIGNALLING UNIT 7. CLASSICAL GPCR SIGNALLING 8. CLASSICAL GPCR SIGNALLING 9. CLASSICAL GPCR SIGNALLINGDE-SENSITIZATION AND RE-SENSITIZATION GRK phosphorylationB-arrestin bindingDecreased signal responseReceptor Sequestration for internalizationDegradationRecycling 10. G PROTEINS Guanosine Nucleotide-Binding Proteins Molecular switches GTPGDP Two Classes: 1. Monomeric Small G Proteins 2. Heteromeric G proteins 11. G PROTEINS 12. G alpha Signalin g 13. GPCRS ACTIVATED BY LIPIDS LPA induce cell migration through RhoA and ROCK activity in breast cancer 14. GPCRS ACTIVATED BY LIPIDSSphingosine-1-phosphate in cancer 15. GPCRS ACTIVATED BY PEPTIDES GRP- Gastrin Releasing Peptide Responsible for growth and angiogenesis in different types of cancer Phospholipases like PLC1 and Kinases like c-Src Antagonists reduces EGFR levels, alteration of MAPK, pAkt, Cox-2 signallingEndothelins ET1 serves a prognostic marker in various cancer DNA synthesis and cell proliferation. Pathway almost similar to GRPs Inhibition of ETAR receptor induced apoptosis and inhibited cell invasion 16. GPCRS ACTIVATED BY HORMONES Angiotensin II signals the Epithelial-toMesenchymal transition through EGFR crosstalk Angiotensin II and bradykinin receptors are overexpressed in Prostate cancer Mediate cell growth through Gq/G13 and RhoAGnRH 1 receptor Gonadotropin releasing hormone receptor one of the smallest GPCR and lacks C-terminus Activation leads to antiproliferative effects in tumor cells through Galpha I GnRH analogues directly suppress the growth of ovarian, breast, prostate cancer 17. GPCRS ACTIVATED BY CHEMOKINE Chemokine and their receptors play a critical role in tumour initiation and progression CXCR1, CXCR2 receptors for IL-8, involved in tumorigenesis, angiogenesis, metastasis etc. CXCL12/SDF1 ligand for CXCR4, involved in Chemo taxis, migration. PGE2, A Cox-2 derived Prostaglandin involved in multiple cancers. 18. GPCRS ACTIVATED BY CHEMOKINE 19. GPCRS AND METASTASIS 20. GPCRS ACTIVATED BY NEUROTRANSMITTERS Adrenaline and Noradrenaline Receptor- Adrenergic receptors (Gs) Tumor Growth, Metastases Somatostatin Receptors (SSTR) Anti-Proliferative, pro-apoptotic 21. GPCR EGFR CROSSTALK 22. GPCRS IN PROSTATE CANCER Role of Circulating factors in prostate cancer growth Involvement of GPCRs in Neoplastic Transformation of Prostate Elevated levels of enzymes that control expression of GPCR ligands. E.g. Kallikrein II PC cells produce increased amount of GPCR ligands. E.g. LPA, ET-1 Malignant PC cells express higher levels of GPCRs like BK-1 receptor, ET1A receptor (exception GPR68,GPR56) 23. GPCRS ACTIVATING ANDROGEN RECEPTORS 24. ORPHAN GPCRS Ligands not identified (140+) De-orphanisation GPR 49- Basal Cell Carcinoma GPR87- Lung, Cervix, skin, urinary bladder, head and neck squamous cell carcinomas GPR56- Tumour Suppressor, Inhibition of angiogenesis and thus extravasation 25. SELECTED REFERENCES Robert T. Dorsam and J. Silvio Gutkind: G-protein-coupled receptors and cancer; Nature Reviews Cancer Volume 7 February 2007 page 79 Yehia Daaka: G Proteins in Cancer: The Prostate Cancer Paradigm: Sci. STKE 2004 (216), re2. Xiao-long TANG et.al. : Orphan G protein-coupled receptors (GPCRs): biological functions and potential drug targets. Acta Pharmacologica Sinica (2012) 33: 363371 ChunMing Teoh et.al. Integrin and GPCR Crosstalk in the Regulation of ASM Contraction Signaling in Asthma, Journal of AllergyVolume 2012, Article ID 341282 Rosamaria LAPPANO, Marcello MAGGIOLINI : GPCRs and cancer Acta Pharmacologica Sinica (2012) 33: 351362 Nigel J. Pyne & Susan Pyne: Sphingosine 1-phosphate and cancer, Nature Reviews Cancer 10, 489-503 (July 2010)