G Protein Coupled Receptors (GPCRs) and Cancer
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  • 1. GPCRS AND CANCER – I SALAM DAYANANDA SINGH
  • 2. ABBREVIATIONS USED GROα Growth-regulated oncogene α GAP GTPase Activating Proteins PAR1 Protease-activated receptor 1 NSAI D Non-steroidal anti-inflammatory drugs SDF1 Stromal Cell Derived Factor 1 ERK Extracellular Receptor Kinase GEFs Guanine nucleotide exchange factor GRP Gastrin Releasing Peptide Cav caveolin-1 GnR H Gonadotropin Releasing hormone GRK GPCR kinase Cox2 Cyclo-oxygenase 2 GSK3 B Glycogen Synthase Kinase 3 B ARA Androgen Receptor Activator Grb2SOS Growth factor receptor-bound protein 2- Son of Sevenless Cdc4 2 Cell Division Control protein homolog 42 PLC-B Phospholipase C beta
  • 3. CONTENTS 1.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 Type Receptor Ligand Process Breast Cancer PAR1 Thrombin Growth, Metastasis EP2, EP4 PGE2 Growth Metastasis LPA1 LPA Growth PAR Thrombin Growth, Migration EP receptors PGE2 Growth Metastasis CXCR4 SDF1 Migration metastasis Angiogenesis LPA1-LPA3 LPA Growth metastasis CXCR2 GROα Growth angiogenesis Eta Endothelin Growth Survival AT1 Angiotensin II Growth LPA1 LPA Growth Invasion Head and Neck Cancer Non-small-cell lung cancer Ovarian Cancer Prostate Cancer
  • 6. BASIC GPCR SIGNALLING UNIT
  • 7. CLASSICAL GPCR SIGNALLING
  • 8. CLASSICAL GPCR SIGNALLING
  • 9. CLASSICAL GPCR SIGNALLING DE-SENSITIZATION AND RE-SENSITIZATION GRK phosphorylation B-arrestin binding Decreased signal response Receptor Sequestration for internalization Degradation Recycling
  • 10. G PROTEINS • Guanosine Nucleotide-Binding Proteins • Molecular switches • GTP GDP • 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 LIPIDS Sphingosine-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 signalling Endothelins • 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 Gαq/Gα13 and RhoA GnRH 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- β –Adrenergic receptors (Gαs) • 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: 363–371 • 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: 351–362 • Nigel J. Pyne & Susan Pyne: Sphingosine 1-phosphate and cancer, Nature Reviews Cancer 10, 489-503 (July 2010)