Skip to main content

Advertisement

SpringerLink
Log in

Revisiting CB1 Receptor as Drug Target in Human Melanoma

  • Research
  • Published:
Pathology & Oncology Research

Abstract

Previous studies have indicated the antitumoral effect of human melanocytes, human melanoma cell lines expressing CB1 receptor (CB1), and of the peritumoral administration of endocannabinoids. In the present study, we systematically screened several human melanoma cell lines for the expression of CNR1 and demonstrated transcription of the authentic gene. The product of CNR1, the CB1 protein, was found localized to the cell membrane as well as to the cytoskeleton. Further, the studied human melanoma cell lines expressed functional CB1 since physiological and synthetic ligands, anandamide (AEA), Met-F-AEA, ACEA and AM251 showed a wide range of biological effects in vitro, for example anti-proliferative, proapoptotic and anti-migratory. More importantly, our studies revealed that systemic administration of a stable CB1 agonist, ACEA, into SCID mice specifically inhibited liver colonization of human melanoma cells. Since therapeutic options for melanoma patients are still very limited, the endocannabinoid-CB1 receptor system may offer a novel target.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

2-AG:

2-arachidonoylglycerol

A:

Adenosine

ACEA:

Arachidonyl-2-chloroethylamide

AEA:

Anandamide

AKT:

Protein kinase B

AM251:

N-piperidinyl-iodophenyl-dichlorophenyl-methylpyrazole-carboxamide

BSA:

Bovine serum albumin

C:

Cytosine

Ca:

Calcium

CB:

Cannabinoid

CB1:

Cannabinoid receptor 1

CB2:

Cannabinoid receptor 2

CNR1:

Gene of cannabinoid receptor 1

cDNA:

Complementary deoxyribonucleic acid

DEPC:

Diethylpyrocarbonate

DMSO:

Dimethyl sulfoxide

DNA:

Deoxyribonucleic acid

COX:

Cyclooxygenase

EDTA:

Ethylenediaminetetraacetic acid

FAAH:

Fatty acid amide hydrolase

FCS:

Fetal calf serum

FITC:

Fluorescein isothiocyanate

G:

Guanine

GPCR:

G protein-coupled receptor

IC50:

Half maximal inhibitory concentration

IFN:

Interferon

IL:

Interleukin

LOX:

Lipooxygenase

MAGL:

Monoacylglycerol lipase

MAPK:

Mitogen-activated protein kinase

Met-F-AEA:

2-methyl-2-fluoro-anandamide

mTOR:

Mammalian target of rapamycin

MTT:

Thiazolyl blue tetrazolium bromide

P:

Probability

PBS:

Phosphate-buffered saline

PCR:

Polymerase chain reaction

PI:

Propidium iodide

PI3K:

Phosphatidylinositol-3 kinase

RAF:

RAF oncogene

RAS:

RAS oncogene

Rb:

Retinoblastoma

RNA:

Ribonucleic acid

SCID:

Severe combined immunodeficiency

T:

Thymine

References

  1. Wang J, Ueda N (2009) Biology of endocannabinoid synthesis system. Prostaglandins Other Lipid Mediat 89:112–119

    Article  PubMed  CAS  Google Scholar 

  2. Flygare J, Sander B (2008) The endocannabinoid system in cancer-potential therapeutic target? Semin Cancer Biol 18:176–189

    Article  PubMed  CAS  Google Scholar 

  3. Mouslech Z, Valla V (2009) Endocannabinoid system: an overview of its potential in current medical practice. Neuro Endocrinol Lett 30:153–179

    PubMed  CAS  Google Scholar 

  4. Bifulco M, Di Marzo V (2002) Targeting the endocannabinoid system in cancer therapy: a call for further research. Nat Med 8:547–550

    Article  PubMed  CAS  Google Scholar 

  5. Alexander A, Smith PF, Rosengren RJ (2009) Cannabinoids in the treatment of cancer. Cancer Lett 285:6–12

    Article  PubMed  CAS  Google Scholar 

  6. Alpini G, Demorrow S (2009) Changes in the endocannabinoid system may give insight into new and effective treatments for cancer. Vitam Horm 81:469–485

    Article  PubMed  CAS  Google Scholar 

  7. Fowler CJ, Gustafsson SB, Chung SC et al (2010) Targeting the endocannabinoid system for the treatment of cancer–a practical view. Curr Top Med Chem 10:814–827

    Article  PubMed  CAS  Google Scholar 

  8. Bifulco M, Malfitano AM, Pisanti S et al (2008) Endocannabinoids in endocrine and related tumours. Endocr Relat Cancer 15:391–408

    Article  PubMed  CAS  Google Scholar 

  9. Portella G, Laezza C, Laccetti P et al (2003) Inhibitory effects of cannabinoid CB1 receptor stimulation on tumor growth and metastatic spreading: actions on signals involved in angiogenesis and metastasis. FASEB J 17:1771–1773

    PubMed  CAS  Google Scholar 

  10. Pisanti S, Bifulco M (2009) Endocannabinoid system modulation in cancer biology and therapy. Pharmacol Res 60:107–116

    Article  PubMed  CAS  Google Scholar 

  11. Bifulco M, Laezza C, Gazzerro P et al (2007) Endocannabinoids as emerging suppressors of angiogenesis and tumor invasion (review). Oncol Rep 17:813–816

    PubMed  CAS  Google Scholar 

  12. Sarfaraz S, Afaq F, Adhami VM et al (2005) Cannabinoid receptor as a novel target for the treatment of prostate cancer. Cancer Res 65:1635–1641

    Article  PubMed  CAS  Google Scholar 

  13. Gazzerro P, Malfitano AM, Proto MC et al (2010) Synergistic inhibition of human colon cancer cell growth by the cannabinoid CB1 receptor antagonist rimonabant and oxaliplatin. Oncol Rep 23:171–175

    PubMed  CAS  Google Scholar 

  14. Biro T, Toth BI, Hasko G et al (2009) The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities. Trends Pharmacol Sci 30:411–420

    Article  PubMed  CAS  Google Scholar 

  15. Casanova ML, Blazquez C, Martinez-Palacio J et al (2003) Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J Clin Invest 111:43–50

    PubMed  CAS  Google Scholar 

  16. Blazquez C, Carracedo A, Barrado L et al (2006) Cannabinoid receptors as novel targets for the treatment of melanoma. FASEB J 20:2633–2635

    Article  PubMed  CAS  Google Scholar 

  17. Sosman JA, Puzanov I (2006) Molecular targets in melanoma from angiogenesis to apoptosis. Clin Cancer Res 12:2376s–2383s

    Article  PubMed  CAS  Google Scholar 

  18. Denkert C, Kobel M, Berger S et al (2001) Expression of cyclooxygenase 2 in human malignant melanoma. Cancer Res 61:303–308

    PubMed  CAS  Google Scholar 

  19. Tabolacci C, Lentini A, Provenzano B et al (2010) Similar antineoplastic effects of nimesulide, a selective COX-2 inhibitor, and prostaglandin E1 on B16-F10 murine melanoma cells. Melanoma Res 20:273–279

    Article  PubMed  CAS  Google Scholar 

  20. Liu B, Khan WA, Hannun YA et al (1995) 12(S)-hydroxyeicosatetraenoic acid and 13(S)-hydroxyoctadecadienoic acid regulation of protein kinase C-alpha in melanoma cells: role of receptor-mediated hydrolysis of inositol phospholipids. Proc Natl Acad Sci U S A 92:9323–9327

    Article  PubMed  CAS  Google Scholar 

  21. Raso E, Dome B, Somlai B et al (2004) Molecular identification, localization and function of platelet-type 12-lipoxygenase in human melanoma progression, under experimental and clinical conditions. Melanoma Res 14:245–250

    Article  PubMed  CAS  Google Scholar 

  22. Ladanyi A, Timar J, Paku S et al (1990) Selection and characterization of human melanoma lines with different liver-colonizing capacity. Int J Cancer 46:456–461

    Article  PubMed  CAS  Google Scholar 

  23. Dome B, Raso E, Dobos J et al (2005) Parallel expression of alphaIIbbeta3 and alphavbeta3 integrins in human melanoma cells upregulates bFGF expression and promotes their angiogenic phenotype. Int J Cancer 116:27–35

    Article  PubMed  Google Scholar 

  24. Deli T, Varga N, Adam A et al (2007) Functional genomics of calcium channels in human melanoma cells. Int J Cancer 121:55–65

    Article  PubMed  CAS  Google Scholar 

  25. Grimaldi C, Pisanti S, Laezza C et al (2006) Anandamide inhibits adhesion and migration of breast cancer cells. Exp Cell Res 312:363–373

    Article  PubMed  CAS  Google Scholar 

  26. Ramer R, Hinz B (2008) Inhibition of cancer cell invasion by cannabinoids via increased expression of tissue inhibitor of matrix metalloproteinases-1. J Natl Cancer Inst 100:59–69

    Article  PubMed  CAS  Google Scholar 

  27. Hersey P, Zhuang L, Zhang XD (2006) Current strategies in overcoming resistance of cancer cells to apoptosis melanoma as a model. Int Rev Cytol 251:131–158

    Article  PubMed  CAS  Google Scholar 

  28. Eberle J, Fecker LF, Hossini AM et al (2008) Apoptosis pathways and oncolytic adenoviral vectors: promising targets and tools to overcome therapy resistance of malignant melanoma. Exp Dermatol 17:1–11

    Article  PubMed  CAS  Google Scholar 

  29. La Porta CA (2009) Mechanism of drug sensitivity and resistance in melanoma. Curr Cancer Drug Targets 9:391–397

    Article  PubMed  Google Scholar 

  30. Sarnataro D, Grimaldi C, Pisanti S et al (2005) Plasma membrane and lysosomal localization of CB1 cannabinoid receptor are dependent on lipid rafts and regulated by anandamide in human breast cancer cells. FEBS Lett 579:6343–6349

    Article  PubMed  CAS  Google Scholar 

  31. Osborne KD, Lee W, Malarkey EB, et al (2009) Dynamic imaging of cannabinoid receptor 1 vesicular trafficking in cultured astrocytes. ASN Neuro 1.

  32. Bari M, Oddi S, De Simone C et al (2008) Type-1 cannabinoid receptors colocalize with caveolin-1 in neuronal cells. Neuropharmacology 54:45–50

    Article  PubMed  CAS  Google Scholar 

  33. Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9:550–562

    Article  PubMed  CAS  Google Scholar 

  34. Liu P, Cheng H, Roberts TM et al (2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 8:627–644

    Article  PubMed  CAS  Google Scholar 

  35. Madhunapantula SV, Robertson GP (2009) The PTEN-AKT3 signaling cascade as a therapeutic target in melanoma. Pigment Cell Melanoma Res 22:400–419

    Article  PubMed  CAS  Google Scholar 

  36. Hudes GR, Berkenblit A, Feingold J et al (2009) Clinical trial experience with temsirolimus in patients with advanced renal cell carcinoma. Semin Oncol 36(Suppl 3):S26–S36

    Article  PubMed  CAS  Google Scholar 

  37. Porta C, Figlin RA (2009) Phosphatidylinositol-3-kinase/Akt signaling pathway and kidney cancer, and the therapeutic potential of phosphatidylinositol-3-kinase/Akt inhibitors. J Urol 182:2569–2577

    Article  PubMed  CAS  Google Scholar 

  38. European public assessment report. Acomplia. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000666/WC500021282.pdf.

Download references

Acknowledgments

This work was supported by TAMOP 4.2.1b, OTKA-NK72595 (JTi) and OTKA-K84173 (JTó).

Author information

Authors and Affiliations

  1. 2nd Department of Pathology, Semmelweis University, Üllői út 93., Budapest, 1091, Hungary

    István Kenessey, Balázs Bánki, Erzsébet Rásó & József Tímár

  2. National Institute of Oncology, Budapest, Hungary

    Ágnes Márk, Norbert Varga, József Tóvári & Andrea Ladányi

Authors
  1. István Kenessey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Balázs Bánki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ágnes Márk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Norbert Varga
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. József Tóvári
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrea Ladányi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Erzsébet Rásó
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. József Tímár
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to István Kenessey.

Additional information

István Kenessey and Balázs Bánki equal contribution.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kenessey, I., Bánki, B., Márk, Á. et al. Revisiting CB1 Receptor as Drug Target in Human Melanoma. Pathol. Oncol. Res. 18, 857–866 (2012). https://doi.org/10.1007/s12253-012-9515-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-012-9515-y

Keywords

Search

Navigation