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
10. CLASSICAL GPCR SIGNALLING
DE-SENSITIZATION AND RE-SENSITIZATION
GRK phosphorylation
B-arrestin binding
Decreased signal response
Receptor Sequestration for internalization
Degradation
Recycling
11. G PROTEINS
• Guanosine Nucleotide-Binding Proteins
• Molecular switches
• GTP
GDP
• Two Classes:
• 1. Monomeric Small G Proteins
• 2. Heteromeric G proteins
16. 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
17. 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
18. 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.
23. 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)
25. 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
26. 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)