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

Fabio Cianchi, Laura Papucci, Nicola Schiavone, Matteo Lulli, Lucia Magnelli, Maria Cristina Vinci, Luca Messerini, Clementina Manera, Elisa Ronconi, Paola Romagnani, Martino Donnini, Giuliano Perigli, Giacomo Trallori, Elisabetta Tanganelli, Sergio Capaccioli, Emanuela Masini

Research output: Contribution to journalArticle

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 CB 2 agonist N-cyclopentyl-7-methyl-1- (2-mor- pholin-4-ylethyl)-1, 8-naphthyridin-4(1H)-on-3-carboxamide (CB13) on tumor cell apoptosis and ceramide and tumor necrosis factor (TNF)-αproduction were evaluated. The knockdown of TNF-αmRNA 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 CB 2 agonist CB13 also reduced the growth of DLD-1 cells in a mouse model of colon cancer. The knockdown of TNF-αmRNA 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, thatTNF-αacts as a link between cannabinoid receptor activation and ceramide production.

Original languageEnglish
Pages (from-to)7691-7700
Number of pages10
JournalClinical Cancer Research
Volume14
Issue number23
DOIs
Publication statusPublished - Dec 1 2008

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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  • Cite this

    Cianchi, F., Papucci, L., Schiavone, N., Lulli, M., Magnelli, L., Vinci, M. C., Messerini, L., Manera, C., Ronconi, E., Romagnani, P., Donnini, M., Perigli, G., Trallori, G., Tanganelli, E., Capaccioli, S., & Masini, E. (2008). Cannabinoid receptor activation induces apoptosis through tumor necrosis factor α-mediated ceramide de novo synthesis in colon cancer cells. Clinical Cancer Research, 14(23), 7691-7700. https://doi.org/10.1158/1078-0432.CCR-08-0799