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)