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

7. BASIC GPCR SIGNALLING UNIT

8. CLASSICAL GPCR SIGNALLING

9. CLASSICAL GPCR SIGNALLING

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

12. G PROTEINS

13. G alpha
Signalin
g

14. GPCRS ACTIVATED BY LIPIDS
• LPA induce cell migration
through RhoA and ROCK
activity in breast cancer

15. GPCRS ACTIVATED BY LIPIDS
Sphingosine-1-phosphate in cancer

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.

19. GPCRS ACTIVATED BY CHEMOKINE

20. GPCRS AND METASTASIS

21. GPCRS ACTIVATED BY
NEUROTRANSMITTERS
• Adrenaline and Noradrenaline
• Receptor- β –Adrenergic receptors (Gαs)
• Tumor Growth, Metastases
• Somatostatin Receptors (SSTR)
• Anti-Proliferative, pro-apoptotic

22. GPCR EGFR CROSSTALK

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)

24. GPCRS ACTIVATING ANDROGEN RECEPTORS

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)