Revisiting CB1 Receptor as Drug Target in Human Melanoma
- 339 Downloads
- 5 Citations
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.
Keywords
CB1 receptor Endocannabinoid Human malignant melanoma MetastasisAbbreviations
- 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
Notes
Acknowledgments
This work was supported by TAMOP 4.2.1b, OTKA-NK72595 (JTi) and OTKA-K84173 (JTó).
References
- 1.Wang J, Ueda N (2009) Biology of endocannabinoid synthesis system. Prostaglandins Other Lipid Mediat 89:112–119PubMedCrossRefGoogle Scholar
- 2.Flygare J, Sander B (2008) The endocannabinoid system in cancer-potential therapeutic target? Semin Cancer Biol 18:176–189PubMedCrossRefGoogle Scholar
- 3.Mouslech Z, Valla V (2009) Endocannabinoid system: an overview of its potential in current medical practice. Neuro Endocrinol Lett 30:153–179PubMedGoogle Scholar
- 4.Bifulco M, Di Marzo V (2002) Targeting the endocannabinoid system in cancer therapy: a call for further research. Nat Med 8:547–550PubMedCrossRefGoogle Scholar
- 5.Alexander A, Smith PF, Rosengren RJ (2009) Cannabinoids in the treatment of cancer. Cancer Lett 285:6–12PubMedCrossRefGoogle Scholar
- 6.Alpini G, Demorrow S (2009) Changes in the endocannabinoid system may give insight into new and effective treatments for cancer. Vitam Horm 81:469–485PubMedCrossRefGoogle 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 10:814–827PubMedCrossRefGoogle Scholar
- 8.Bifulco M, Malfitano AM, Pisanti S et al (2008) Endocannabinoids in endocrine and related tumours. Endocr Relat Cancer 15:391–408PubMedCrossRefGoogle 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 17:1771–1773PubMedGoogle Scholar
- 10.Pisanti S, Bifulco M (2009) Endocannabinoid system modulation in cancer biology and therapy. Pharmacol Res 60:107–116PubMedCrossRefGoogle Scholar
- 11.Bifulco M, Laezza C, Gazzerro P et al (2007) Endocannabinoids as emerging suppressors of angiogenesis and tumor invasion (review). Oncol Rep 17:813–816PubMedGoogle 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 65:1635–1641PubMedCrossRefGoogle 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 23:171–175PubMedGoogle 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 30:411–420PubMedCrossRefGoogle 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 111:43–50PubMedGoogle Scholar
- 16.Blazquez C, Carracedo A, Barrado L et al (2006) Cannabinoid receptors as novel targets for the treatment of melanoma. FASEB J 20:2633–2635PubMedCrossRefGoogle Scholar
- 17.Sosman JA, Puzanov I (2006) Molecular targets in melanoma from angiogenesis to apoptosis. Clin Cancer Res 12:2376s–2383sPubMedCrossRefGoogle Scholar
- 18.Denkert C, Kobel M, Berger S et al (2001) Expression of cyclooxygenase 2 in human malignant melanoma. Cancer Res 61:303–308PubMedGoogle 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 20:273–279PubMedCrossRefGoogle 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 92:9323–9327PubMedCrossRefGoogle 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 14:245–250PubMedCrossRefGoogle 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 46:456–461PubMedCrossRefGoogle 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 116:27–35PubMedCrossRefGoogle Scholar
- 24.Deli T, Varga N, Adam A et al (2007) Functional genomics of calcium channels in human melanoma cells. Int J Cancer 121:55–65PubMedCrossRefGoogle Scholar
- 25.Grimaldi C, Pisanti S, Laezza C et al (2006) Anandamide inhibits adhesion and migration of breast cancer cells. Exp Cell Res 312:363–373PubMedCrossRefGoogle 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 100:59–69PubMedCrossRefGoogle 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 251:131–158PubMedCrossRefGoogle 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 17:1–11PubMedCrossRefGoogle Scholar
- 29.La Porta CA (2009) Mechanism of drug sensitivity and resistance in melanoma. Curr Cancer Drug Targets 9:391–397PubMedCrossRefGoogle 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 579:6343–6349PubMedCrossRefGoogle 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.Google Scholar
- 32.Bari M, Oddi S, De Simone C et al (2008) Type-1 cannabinoid receptors colocalize with caveolin-1 in neuronal cells. Neuropharmacology 54:45–50PubMedCrossRefGoogle Scholar
- 33.Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9:550–562PubMedCrossRefGoogle Scholar
- 34.Liu P, Cheng H, Roberts TM et al (2009) Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 8:627–644PubMedCrossRefGoogle Scholar
- 35.Madhunapantula SV, Robertson GP (2009) The PTEN-AKT3 signaling cascade as a therapeutic target in melanoma. Pigment Cell Melanoma Res 22:400–419PubMedCrossRefGoogle 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–S36PubMedCrossRefGoogle 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 182:2569–2577PubMedCrossRefGoogle 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.