GPCRS AND CANCER – I
SALAM DAYANANDA SINGH
ABBREVIATIONS USED
GROα Growth-regulated oncogene α GAP GTPase Activating Proteins
PAR1 Protease-activated receptor 1 NSAID
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 GnRH
Gonadotropin Releasing hormone
GRK GPCR kinase Cox-2
Cyclo-oxygenase 2
GSK3B
Glycogen Synthase Kinase 3 B ARA Androgen Receptor Activator
Grb2-SOS
Growth factor receptor-bound protein 2- Son of Sevenless
Cdc42
Cell Division Control protein homolog 42
PLC-B Phospholipase C beta
CONTENTS
1.Introduction2.Classical GPCR Signalling3.G proteins4.GPCR and its Ligands5.GPCRs in Prostate Cancer6.Orphan GPCRs7.References
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
GPCR AND CANCERCancer Type Receptor Ligand Process
Breast Cancer PAR1 Thrombin Growth, Metastasis
EP2, EP4 PGE2 Growth Metastasis
Head and Neck Cancer LPA1 LPA Growth
PAR Thrombin Growth, Migration
Non-small-cell lung cancer
EP receptors PGE2 Growth Metastasis
CXCR4 SDF1 Migration metastasis Angiogenesis
Ovarian Cancer LPA1-LPA3 LPA Growth metastasis
CXCR2 GROα Growth angiogenesis
Prostate Cancer Eta Endothelin Growth Survival
AT1 Angiotensin II Growth
LPA1 LPA Growth Invasion
BASIC GPCR SIGNALLING UNIT
CLASSICAL GPCR SIGNALLING
CLASSICAL GPCR SIGNALLING
DE-SENSITIZATION AND RE-SENSITIZATIONCLASSICAL GPCR SIGNALLING
GRK phosphorylation
B-arrestin binding
Decreased signal response
Receptor Sequestration for internalization
RecyclingDegradation
G PROTEINS
• Guanosine Nucleotide-Binding Proteins
• Molecular switches
• GTP GDP
• Two Classes: • 1. Monomeric Small G Proteins • 2. Heteromeric G proteins
G PROTEINS
G alpha Signaling
GPCRS ACTIVATED BY LIPIDS
• LPA induce cell migration through RhoA and ROCK activity in breast cancer
GPCRS ACTIVATED BY LIPIDS
Sphingosine-1-phosphate in cancer
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
GPCRS ACTIVATED BY HORMONES
• Angiotensin II signals the Epithelial-to-Mesenchymal 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
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.
GPCRS ACTIVATED BY CHEMOKINE
GPCRS AND METASTASIS
GPCRS ACTIVATED BY NEUROTRANSMITTERS
• Adrenaline and Noradrenaline
• Receptor- β –Adrenergic receptors (Gαs)
• Tumor Growth, Metastases
• Somatostatin Receptors (SSTR)
• Anti-Proliferative, pro-apoptotic
GPCR EGFR CROSSTALK
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)
GPCRS ACTIVATING ANDROGEN RECEPTORS
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
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)