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Cannabinoid receptor activation induces apoptosis through tumor necrosis factor alpha-mediated ceramide de novo synthesis in colon cancer cells.

Abstract

PURPOSE

Cannabinoids have been recently proposed as a new family of potential antitumor agents. The present study was undertaken to investigate the expression of the two cannabinoid receptors, CB1 and CB2, in colorectal cancer and to provide new insight into the molecular pathways underlying the apoptotic activity induced by their activation.

EXPERIMENTAL DESIGN

Cannabinoid receptor expression was investigated in both human cancer specimens and in the DLD-1 and HT29 colon cancer cell lines. The effects of the CB1 agonist arachinodyl-2'-chloroethylamide and the CB2 agonist N-cyclopentyl-7-methyl-1-(2-morpholin-4-ylethyl)-1,8-naphthyridin-4(1H)-on-3-carboxamide (CB13) on tumor cell apoptosis and ceramide and tumor necrosis factor (TNF)-alpha production were evaluated. The knockdown of TNF-alpha mRNA was obtained with the use of selective small interfering RNA.

RESULTS

We show that the CB1 receptor was mainly expressed in human normal colonic epithelium whereas tumor tissue was strongly positive for the CB2 receptor. The activation of the CB1 and, more efficiently, of the CB2 receptors induced apoptosis and increased ceramide levels in the DLD-1 and HT29 cells. Apoptosis was prevented by the pharmacologic inhibition of ceramide de novo synthesis. The CB2 agonist CB13 also reduced the growth of DLD-1 cells in a mouse model of colon cancer. The knockdown of TNF-alpha mRNA abrogated the ceramide increase and, therefore, the apoptotic effect induced by cannabinoid receptor activation.

CONCLUSIONS

The present study shows that either CB1 or CB2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells. Our data unveiled, for the first time, that TNF-alpha acts as a link between cannabinoid receptor activation and ceramide production.

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  • Authors+Show Affiliations

    ,

    Department of Medical and Surgical Critical Care, University of Florence, Florence, Italy.

    , , , , , , , , , , , , , ,

    Source

    MeSH

    Animals
    Apoptosis
    Blotting, Western
    Cell Line, Tumor
    Ceramides
    Colonic Neoplasms
    Enzyme-Linked Immunosorbent Assay
    Flow Cytometry
    Fluorescent Antibody Technique
    Humans
    Immunohistochemistry
    Mice
    Mice, Nude
    RNA, Small Interfering
    Receptor, Cannabinoid, CB1
    Receptor, Cannabinoid, CB2
    Reverse Transcriptase Polymerase Chain Reaction
    Transfection
    Tumor Necrosis Factor-alpha

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    19047095

    Citation

    Cianchi, Fabio, et al. "Cannabinoid Receptor Activation Induces Apoptosis Through Tumor Necrosis Factor Alpha-mediated Ceramide De Novo Synthesis in Colon Cancer Cells." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 14, no. 23, 2008, pp. 7691-700.
    Cianchi F, Papucci L, Schiavone N, et al. Cannabinoid receptor activation induces apoptosis through tumor necrosis factor alpha-mediated ceramide de novo synthesis in colon cancer cells. Clin Cancer Res. 2008;14(23):7691-700.
    Cianchi, F., Papucci, L., Schiavone, N., Lulli, M., Magnelli, L., Vinci, M. C., ... Masini, E. (2008). Cannabinoid receptor activation induces apoptosis through tumor necrosis factor alpha-mediated ceramide de novo synthesis in colon cancer cells. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 14(23), pp. 7691-700. doi:10.1158/1078-0432.CCR-08-0799.
    Cianchi F, et al. Cannabinoid Receptor Activation Induces Apoptosis Through Tumor Necrosis Factor Alpha-mediated Ceramide De Novo Synthesis in Colon Cancer Cells. Clin Cancer Res. 2008 Dec 1;14(23):7691-700. PubMed PMID: 19047095.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Cannabinoid receptor activation induces apoptosis through tumor necrosis factor alpha-mediated ceramide de novo synthesis in colon cancer cells. AU - Cianchi,Fabio, AU - Papucci,Laura, AU - Schiavone,Nicola, AU - Lulli,Matteo, AU - Magnelli,Lucia, AU - Vinci,Maria Cristina, AU - Messerini,Luca, AU - Manera,Clementina, AU - Ronconi,Elisa, AU - Romagnani,Paola, AU - Donnini,Martino, AU - Perigli,Giuliano, AU - Trallori,Giacomo, AU - Tanganelli,Elisabetta, AU - Capaccioli,Sergio, AU - Masini,Emanuela, PY - 2008/12/3/pubmed PY - 2009/2/6/medline PY - 2008/12/3/entrez SP - 7691 EP - 700 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin. Cancer Res. VL - 14 IS - 23 N2 - PURPOSE: Cannabinoids have been recently proposed as a new family of potential antitumor agents. The present study was undertaken to investigate the expression of the two cannabinoid receptors, CB1 and CB2, in colorectal cancer and to provide new insight into the molecular pathways underlying the apoptotic activity induced by their activation. EXPERIMENTAL DESIGN: Cannabinoid receptor expression was investigated in both human cancer specimens and in the DLD-1 and HT29 colon cancer cell lines. The effects of the CB1 agonist arachinodyl-2'-chloroethylamide and the CB2 agonist N-cyclopentyl-7-methyl-1-(2-morpholin-4-ylethyl)-1,8-naphthyridin-4(1H)-on-3-carboxamide (CB13) on tumor cell apoptosis and ceramide and tumor necrosis factor (TNF)-alpha production were evaluated. The knockdown of TNF-alpha mRNA was obtained with the use of selective small interfering RNA. RESULTS: We show that the CB1 receptor was mainly expressed in human normal colonic epithelium whereas tumor tissue was strongly positive for the CB2 receptor. The activation of the CB1 and, more efficiently, of the CB2 receptors induced apoptosis and increased ceramide levels in the DLD-1 and HT29 cells. Apoptosis was prevented by the pharmacologic inhibition of ceramide de novo synthesis. The CB2 agonist CB13 also reduced the growth of DLD-1 cells in a mouse model of colon cancer. The knockdown of TNF-alpha mRNA abrogated the ceramide increase and, therefore, the apoptotic effect induced by cannabinoid receptor activation. CONCLUSIONS: The present study shows that either CB1 or CB2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells. Our data unveiled, for the first time, that TNF-alpha acts as a link between cannabinoid receptor activation and ceramide production. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/19047095/Cannabinoid_receptor_activation_induces_apoptosis_through_tumor_necrosis_factor_alpha_mediated_ceramide_de_novo_synthesis_in_colon_cancer_cells_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=19047095 DB - PRIME DP - Unbound Medicine ER -