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G-Protein Coupled Receptors in Cancer and Targeting Strategies

  • Aditya Narvekar
  • Ashu Srivastav
  • Aparna Tripathi
  • Padma V. Devarajan
  • Ratnesh JainEmail author
  • Prajakta DandekarEmail author
Chapter
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 39)

Abstract

G-protein-coupled receptors (GPCRs) play a significant role in a myriad of physiological processes. Therefore, deregulation of GPCR function is implicated in various cancers, making them a suitable target for targeted therapy. Many studies have indicated a key role of GPCRs in cancer initiation, progression, tumorigenesis, and metastases. This manuscript will discuss a few examples of GPCRs involved in cancer with respect to their structure activity, mechanism of binding, ligands explored, and antagonists, along with the targeting strategies. Many clinical trials with different GPCR targeting drugs are ongoing and are expected to contribute to existing anticancer therapeutics. The research in the area of targeting GPCR is anticipated to exploit their potential as pharmacologically important targets.

Keywords

G-protein-coupled receptors (GPCRs) Targeting Protease-activated receptors Lysophosphatidic acid receptor Frizzled receptor 

Abbreviations

APC

Activated protein C

APC

Adenomatous polyposis coli

ASA

Acetylsalicylic acid

AXIN

Axis inhibition protein

CAD

Coronary artery diseases

cAMP

Cyclic adenosine monophosphate

CaR

Calcium sensing

CBP

CREB-binding protein

CK1

Casein kinase 1

CRD

Cysteine-rich domain

DAG

Diacylglycerol

DKK

Dickkopf

DSH

Dishevelled

DSPE-PEG

1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol)

ECL

Extracellular loops

EDG

Endothelial differentiation gene

EMT

Epithelial-mesenchymal transition

EPCR

Endothelial protein C receptor

FRET

Fluorescence resonance energy transfer

FZD

Frizzled receptor

FZD7-NS

FZD7 antibody-nanoshell conjugate

G2A

G2 accumulation

GDP

Guanosine diphosphate

GPCRs

G-protein-coupled receptors

GSK

Glycogen synthase kinas

GTP

Guanosine triphosphate

HCC

Hepatocellular carcinoma

IC

Inhibitory concentration

ICL

Intracellular loops

IP3

Inositol triphosphate

LEF/TCF

Lymphoid enhancer factor/T-cell factor

LPA

Lysophosphatidic acid

LRP

Lipoprotein receptor-related proteins

LRR

Leucine-rich repeat-containing receptors

MAPK

Mitogen-activated protein kinase

MI

Myocardial infarction

MMP

Matrix metalloproteases

mTORC2

Mammalian target of rapamycin complex 2

NDP gene

Norrie disease protein gene

NF-κB

Nuclear factor kappa light chain enhancer of activated B cells

NIR

Near-infrared radiation

NT

N-terminal sequence

OMP-18R5

Vantictumab, a monoclonal antibody

OMP-54F28

A novel recombinant fusion protein

PAP

Protease activable prodrugs

PAR

Protease-activated receptor

PC

Planar cell polarity

PEG

Polyethylene glycol

PI3K-AKT

Phosphatidylinositol 3-kinase-protein kinase B

PIP 2

Phosphoinositol

PK

Protein kinase

PKC

Protein kinase C

PLC

Phospholipase C

PLC-β

Phospholipase C-β

PORC

Porcupine

RAC

Ras-related C3 botulinum toxin substrate

RAF-MEK-MAPK

Rapidly accelerated fibrosarcoma-MAPK ERK kinase-mitogen-activated protein kinase

Rho

RAS homologous protein family

Ryk and Ror2

Tyrosine kinase receptor

SFRP

Secreted frizzled-related protein

sFZD7

Soluble frizzled receptor 7 antagonist decoy receptor

TcdB

Clostridium difficile toxin B

TLS

Tethered ligand sequence

TM

Transmembrane

TSH

Thyroid-stimulating hormone

UCNP

Up-conversion nanoparticles

VEGF

Vascular endothelial growth factor;

WNT

Wingless type protein

XWnt

Xenopus wingless type protein

References

  1. 1.
    Insel PA, Sriram K, Wiley SZ, French RP, Lowy AM. GPCRs as novel potential therapeutic targets in cancer. FASEB J. 2017;31(1_supplement):671.10.Google Scholar
  2. 2.
    Zalewska M, Siara M, Sajewicz W. G protein-coupled receptors: abnormalities in signal transmission, disease states and pharmacotherapy. Acta Pol Pharm. 2014;71(2):229–43.PubMedGoogle Scholar
  3. 3.
    Hauser AS, Chavali S, Masuho I, Jahn LJ, Martemyanov KA, Gloriam DE, et al. Pharmacogenomics of GPCR drug targets. Cell. 2018;172(1–2):41–54. e19.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Pierce KL, Premont RT, Lefkowitz RJ. Signalling: seven-transmembrane receptors. Nat Rev Mol Cell Biol. 2002;3(9):639.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    DeFea K, Vaughn Z, O’bryan E, Nishijima D, Dery O, Bunnett N. The proliferative and antiapoptotic effects of substance P are facilitated by formation of a β-arrestin-dependent scaffolding complex. Proc Natl Acad Sci. 2000;97(20):11086–91.PubMedCrossRefGoogle Scholar
  6. 6.
    Bar-Shavit R, Maoz M, Kancharla A, Nag J, Agranovich D, Grisaru-Granovsky S, et al. G protein-coupled receptors in cancer. Int J Mol Sci. 2016;17(8):1320.PubMedCentralCrossRefPubMedGoogle Scholar
  7. 7.
    Déry O, Corvera CU, Steinhoff M, Bunnett NW. Proteinase-activated receptors: novel mechanisms of signaling by serine proteases. Am J Phys Cell Phys. 1998;274(6):C1429–C52.CrossRefGoogle Scholar
  8. 8.
    Wojtukiewicz MZ, Hempel D, Sierko E, Tucker SC, Honn KV. Protease-activated receptors (PARs)—biology and role in cancer invasion and metastasis. Cancer Metastasis Rev. 2015;34(4):775–96.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Lee S-C, Fujiwara Y, Tigyi GJ. Uncovering unique roles of LPA receptors in the tumor microenvironment. Receptors Clin Investig. 2015;2(1).Google Scholar
  10. 10.
    Altman MK, Gopal V, Jia W, Yu S, Hall H, Mills GB, et al. Targeting melanoma growth and viability reveals dualistic functionality of the phosphonothionate analogue of carba cyclic phosphatidic acid. Mol Cancer. 2010;9(1):140.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Zeng C-M, Chen Z, Fu L. Frizzled receptors as potential therapeutic targets in human cancers. Int J Mol Sci. 2018;19(5):1543.PubMedCentralCrossRefGoogle Scholar
  12. 12.
    Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P, et al. Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci. 2001;98(24):13790–5.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Macfarlane SR, Seatter MJ, Kanke T, Hunter GD, Plevin R. Proteinase-activated receptors. Pharmacol Rev. 2001;53(2):245–82.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Coughlin SR. Thrombin signalling and protease-activated receptors. Nature. 2000;407(6801):258.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Gieseler F, Ungefroren H, Settmacher U, Hollenberg MD, Kaufmann R. Proteinase-activated receptors (PARs)–focus on receptor-receptor-interactions and their physiological and pathophysiological impact. Cell Commun Signal. 2013;11(1):86.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Lerner DJ, Chen M, Tram T, Coughlin SR. Agonist recognition by proteinase-activated receptor 2 and thrombin receptor Importance of extracellular loop interactions for receptor function. J Biol Chem. 1996;271(24):13943–7.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Nguyen C, Coelho A-M, Grady E, Compton SJ, Wallace JL, Hollenberg MD, et al. Colitis induced by proteinase-activated receptor-2 agonists is mediated by a neurogenic mechanism. Can J Physiol Pharmacol. 2003;81(9):920–7.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Wong SK-F. G protein selectivity is regulated by multiple intracellular regions of GPCRs. Neurosignals. 2003;12(1):1–12.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Zhang C, Srinivasan Y, Arlow DH, Fung JJ, Palmer D, Zheng Y, et al. High-resolution crystal structure of human protease-activated receptor 1. Nature. 2012;492(7429):387.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Wu CC, Huang SW, Hwang TL, Kuo SC, Lee FY, Teng CM. YD-3, a novel inhibitor of protease-induced platelet activation. Br J Pharmacol. 2000;130(6):1289–96.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Hamilton JR, Trejo J. Challenges and opportunities in protease-activated receptor drug development. Annu Rev Pharmacol Toxicol. 2017;57:349–73.PubMedCrossRefGoogle Scholar
  22. 22.
    Flaumenhaft R, De Ceunynck K. Targeting PAR1: now what? Trends Pharmacol Sci. 2017;38(8):701–16.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Austin KM, Covic L, Kuliopulos A. Matrix metalloproteases and PAR1 activation. Blood. 2013;121(3):431–9.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Riewald M, Petrovan RJ, Donner A, Mueller BM, Ruf W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science. 2002;296(5574):1880–2.PubMedCrossRefGoogle Scholar
  25. 25.
    Zhao P, Metcalf M, Bunnett NW. Biased signaling of protease-activated receptors. Front Endocrinol. 2014;5:67.CrossRefGoogle Scholar
  26. 26.
    Feistritzer C, Riewald M. Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1–phosphate receptor-1 cross activation. Blood. 2005;105(8):3178–84.PubMedCrossRefGoogle Scholar
  27. 27.
    Soh UJ, Trejo J. Activated protein C promotes protease-activated receptor-1 cytoprotective signaling through β-arrestin and dishevelled-2 scaffolds. Proc Natl Acad Sci. 2011;108(50):E1372–E80.PubMedCrossRefGoogle Scholar
  28. 28.
    Weidle UH, Tiefenthaler G, Georges G. Proteases as activators for cytotoxic prodrugs in antitumor therapy. Cancer Genomics Proteomics. 2014;11(2):67–79.PubMedGoogle Scholar
  29. 29.
    Choi KY, Swierczewska M, Lee S, Chen X. Protease-activated drug development. Theranostics. 2012;2(2):156.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Chan Y-C, Chen C-W, Chan M-H, Chang Y-C, Chang W-M, Chi L-H, et al. MMP2-sensing up-conversion nanoparticle for fluorescence biosensing in head and neck cancer cells. Biosens Bioelectron. 2016;80:131–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Chan Y-C, Hsiao M. Protease-activated nanomaterials for targeted cancer theranostics. Nanomedicine. 2017;12(18):2153–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Yung YC, Stoddard NC, Chun J. LPA receptor signaling: pharmacology, physiology, and pathophysiology. J Lipid Res. 2014;55(7):1192–214.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Murph MM, Radhakrishna H. LPAR1 (lysophosphatidic acid receptor 1). Atlas of Genetics and Cytogenetics in Oncology and Haematology. 2010.Google Scholar
  34. 34.
    Fukushima N, Ishii S, Tsujiuchi T, Kagawa N, Katoh K. Comparative analyses of lysophosphatidic acid receptor-mediated signaling. Cell Mol Life Sci. 2015;72(12):2377–94.PubMedCrossRefGoogle Scholar
  35. 35.
    Xiang SY, Dusaban SS, Brown JH. Lysophospholipid receptor activation of RhoA and lipid signaling pathways. Biochim Biophys Acta (BBA) Mol Cell Biol Lipids. 2013;1831(1):213–22.CrossRefGoogle Scholar
  36. 36.
    Hildebrandt J-P. Lysophosphatidic acid induces inositol phosphate and calcium signals in exocrine cells from the avian nasal salt gland. J Membr Biol. 1995;144(1):49–58.PubMedCrossRefGoogle Scholar
  37. 37.
    Fang X, Yu S, LaPushin R, Lu Y, Furui T, Penn LZ, et al. Lysophosphatidic acid prevents apoptosis in fibroblasts via G (i)-protein-mediated activation of mitogen-activated protein kinase. Biochem J. 2000;352(Pt 1):135.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Parrill AL, Tigyi G. Integrating the puzzle pieces: the current atomistic picture of phospholipid–G protein coupled receptor interactions. Biochim Biophys Acta (BBA) Mol Cell Biol Lipids. 2013;1831(1):2–12.CrossRefGoogle Scholar
  39. 39.
    Endo T, Kano K, Motoki R, Hama K, Okudaira S, Ishida M, et al. Lysophosphatidylmethanol is a pan lysophosphatidic acid receptor agonist and is produced by autotaxin in blood. J Biochem. 2009;146(2):283–93.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Parrill AL. Design of anticancer lysophosphatidic acid agonists and antagonists. Future Med Chem. 2014;6(8):871–83.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Tigyi G. Aiming drug discovery at lysophosphatidic acid targets. Br J Pharmacol. 2010;161(2):241–70.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Lynch KR, Macdonald TL. Structure–activity relationships of lysophosphatidic acid analogs. Biochim Biophys Acta (BBA) Mol Cell Biol Lipids. 2002;1582(1–3):289–94.CrossRefGoogle Scholar
  43. 43.
    Tokumura A, Kume T, Fukuzawa K, Tsukatani H. Cardiovascular effects of lysophosphatidic acid and its structural analogs in rats. J Pharmacol Exp Ther. 1981;219(1):219–24.PubMedGoogle Scholar
  44. 44.
    Kiss GN, Fells JI, Gupte R, Lee S-C, Liu J, Nusser N, et al. Virtual screening for LPA2-specific agonists identifies a nonlipid compound with antiapoptotic actions. Mol Pharmacol. 2012;82(6):1162–73.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Kiss GN, Lee S-C, Fells JI, Liu J, Valentine WJ, Fujiwara Y, et al. Mitigation of radiation injury by selective stimulation of the LPA2 receptor. Biochim Biophys Acta (BBA) Mol Cell Biol Lipids. 2013;1831(1):117–25.CrossRefGoogle Scholar
  46. 46.
    Zhang H, Xu X, Gajewiak J, Tsukahara R, Fujiwara Y, Liu J, et al. Dual activity lysophosphatidic acid receptor pan-antagonist/autotaxin inhibitor reduces breast cancer cell migration in vitro and causes tumor regression in vivo. Cancer Res. 2009;69(13):5441–9.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Xu X, Prestwich GD. Inhibition of tumor growth and angiogenesis by a lysophosphatidic acid antagonist in an engineered three-dimensional lung cancer xenograft model. Cancer. 2010;116(7):1739–50.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Xu Y, Jiang G, Tsukahara R, Fujiwara Y, Tigyi G, Prestwich GD. Phosphonothioate and fluoromethylene phosphonate analogues of cyclic phosphatidic acid: novel antagonists of lysophosphatidic acid receptors. J Med Chem. 2006;49(17):5309–15.PubMedCrossRefGoogle Scholar
  49. 49.
    Huang H-C, Klein PS. The Frizzled family: receptors for multiple signal transduction pathways. Genome Biol. 2004;5(7):234.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    http://atlasgeneticsoncology.org/Genes/FZD5ID47614ch2q33.htmlGoogle Scholar
  51. 51.
    Nile AH, Mukund S, Stanger K, Wang W, Hannoush RN. Unsaturated fatty acyl recognition by Frizzled receptors mediates dimerization upon Wnt ligand binding. Proc Natl Acad Sci. 2017;114(16):4147–52.PubMedCrossRefGoogle Scholar
  52. 52.
    Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. 2017;36(11):1461.PubMedCrossRefGoogle Scholar
  53. 53.
    Breuhahn K, Longerich T, Schirmacher P. Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene. 2006;25(27):3787.PubMedCrossRefGoogle Scholar
  54. 54.
    Janda CY, Waghray D, Levin AM, Thomas C, Garcia KC. Structural basis of Wnt recognition by Frizzled. Science. 2012;337(6090):59–64.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Lee H-J, Bao J, Miller A, Zhang C, Wu J, Baday YC, et al. Structure-based discovery of novel small molecule Wnt signaling inhibitors by targeting the cysteine-rich domain of frizzled. J Biol Chem. 2015;290(51):30596–606.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017;169(6):985–99.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Zhang X, Dong S, Xu F. Structural and druggability landscape of Frizzled G protein-coupled receptors. Trends Biochem Sci. 2018;43:1033.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Chang T-H, Hsieh F-L, Zebisch M, Harlos K, Elegheert J, Jones EY. Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan. elife. 2015;4:e06554.PubMedCentralCrossRefGoogle Scholar
  59. 59.
    ChemSpider.Google Scholar
  60. 60.
  61. 61.
    Janda CY, Dang LT, You C, Chang J, de Lau W, Zhong ZA, et al. Surrogate Wnt agonists that phenocopy canonical Wnt and β-catenin signalling. Nature. 2017;545(7653):234.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Kim Y-M, Kahn M. The role of the Wnt signaling pathway in cancer stem cells: prospects for drug development. Res Rep Biochem. 2014;4:1.PubMedPubMedCentralGoogle Scholar
  63. 63.
    Le PN, McDermott JD, Jimeno A. Targeting the Wnt pathway in human cancers: therapeutic targeting with a focus on OMP-54F28. Pharmacol Ther. 2015;146:1–11.PubMedCrossRefGoogle Scholar
  64. 64.
    Krishnamurthy N, Kurzrock R. Targeting the Wnt/beta-catenin pathway in cancer: update on effectors and inhibitors. Cancer Treat Rev. 2018;62:50–60.PubMedCrossRefGoogle Scholar
  65. 65.
    Riley RS, Day ES. Frizzled7 antibody-functionalized nanoshells enable multivalent binding for Wnt signaling inhibition in triple negative breast cancer cells. Small. 2017;13(26):1700544.CrossRefGoogle Scholar
  66. 66.
    clinicaltrials.gov. U.S. National Library of Medicine. NIH.

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Aditya Narvekar
    • 1
  • Ashu Srivastav
    • 3
  • Aparna Tripathi
    • 1
  • Padma V. Devarajan
    • 2
  • Ratnesh Jain
    • 3
    Email author
  • Prajakta Dandekar
    • 2
    Email author
  1. 1.Department of Pharmaceutical Sciences & TechnologyInstitute of Chemical Technology, MatungaMumbaiIndia
  2. 2.Department of Pharmaceutical SciencesInsitute of Chemical Technology, Deemed University, Elite Status and Centre of Excellence, Government of MaharashtraMumbaiIndia
  3. 3.Department of Chemical EngineeringInstitute of Chemical Technology, MatungaMumbaiIndia

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