GPCRS AND CANCER – I
SALAM DAYANANDA SINGH
ABBREVIATIONS USED
GROα

Growth-regulated oncogene α

GAP

GTPase Activating Proteins

PAR1

Protease-activated receptor 1...
CONTENTS

1.Introduction
2.Classical GPCR Signalling
3.G proteins
4.GPCR and its Ligands
5.GPCRs in Prostate Cancer
6.Orph...
INTRODUCTION
• GPCR-G-Protein Coupled Receptor

• Gatekeepers
• More than 900 genes, 1% of the total human genome
• Signal...
GPCR AND CANCER
Cancer Type

Receptor

Ligand

Process

Breast Cancer

PAR1

Thrombin

Growth, Metastasis

EP2, EP4

PGE2
...
BASIC GPCR SIGNALLING UNIT
CLASSICAL GPCR SIGNALLING
CLASSICAL GPCR SIGNALLING
CLASSICAL GPCR SIGNALLING

DE-SENSITIZATION AND RE-SENSITIZATION
GRK phosphorylation

B-arrestin binding

Decreased signal...
G PROTEINS
• Guanosine Nucleotide-Binding Proteins
• Molecular switches
• GTP

GDP

• Two Classes:
• 1. Monomeric Small G ...
G PROTEINS
G alpha
Signalin
g
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 t...
GPCRS ACTIVATED BY HORMONES
• Angiotensin II signals the Epithelial-toMesenchymal transition through EGFR crosstalk
• Angi...
GPCRS ACTIVATED BY CHEMOKINE

 Chemokine and their receptors play a critical role in tumour initiation and progression
 ...
GPCRS ACTIVATED BY CHEMOKINE
GPCRS AND METASTASIS
GPCRS ACTIVATED BY
NEUROTRANSMITTERS
• Adrenaline and Noradrenaline
• Receptor- β –Adrenergic receptors (Gαs)

• Tumor Gro...
GPCR EGFR CROSSTALK
GPCRS IN PROSTATE CANCER
• Role of Circulating factors in prostate cancer growth
• Involvement of GPCRs in Neoplastic Tran...
GPCRS ACTIVATING ANDROGEN RECEPTORS
ORPHAN GPCRS

• Ligands not identified (140+)
• De-orphanisation
• GPR 49- Basal Cell Carcinoma
• GPR87- Lung, Cervix, ski...
SELECTED REFERENCES
• Robert T. Dorsam and J. Silvio Gutkind: G-protein-coupled receptors and cancer; Nature Reviews
Cance...
G Protein Coupled Receptors (GPCRs) and Cancer
Upcoming SlideShare
Loading in...5
×

G Protein Coupled Receptors (GPCRs) and Cancer

2,424

Published on

Published in: Health & Medicine, Technology
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
2,424
On Slideshare
0
From Embeds
0
Number of Embeds
1
Actions
Shares
0
Downloads
72
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide
  • djhfdjflkjdlfjdlkfj
  • G Protein Coupled Receptors (GPCRs) and Cancer

    1. 1. GPCRS AND CANCER – I SALAM DAYANANDA SINGH
    2. 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. 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. 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. 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. 6. BASIC GPCR SIGNALLING UNIT
    7. 7. CLASSICAL GPCR SIGNALLING
    8. 8. CLASSICAL GPCR SIGNALLING
    9. 9. CLASSICAL GPCR SIGNALLING DE-SENSITIZATION AND RE-SENSITIZATION GRK phosphorylation B-arrestin binding Decreased signal response Receptor Sequestration for internalization Degradation Recycling
    10. 10. G PROTEINS • Guanosine Nucleotide-Binding Proteins • Molecular switches • GTP GDP • Two Classes: • 1. Monomeric Small G Proteins • 2. Heteromeric G proteins
    11. 11. G PROTEINS
    12. 12. G alpha Signalin g
    13. 13. GPCRS ACTIVATED BY LIPIDS • LPA induce cell migration through RhoA and ROCK activity in breast cancer
    14. 14. GPCRS ACTIVATED BY LIPIDS Sphingosine-1-phosphate in cancer
    15. 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. 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. 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. 18. GPCRS ACTIVATED BY CHEMOKINE
    19. 19. GPCRS AND METASTASIS
    20. 20. GPCRS ACTIVATED BY NEUROTRANSMITTERS • Adrenaline and Noradrenaline • Receptor- β –Adrenergic receptors (Gαs) • Tumor Growth, Metastases • Somatostatin Receptors (SSTR) • Anti-Proliferative, pro-apoptotic
    21. 21. GPCR EGFR CROSSTALK
    22. 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. 23. GPCRS ACTIVATING ANDROGEN RECEPTORS
    24. 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. 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)
    1. A particular slide catching your eye?

      Clipping is a handy way to collect important slides you want to go back to later.

    ×