Cannabinoid Receptor Activation Induces Apoptosis through Tumor Necrosis Factor α–Mediated Ceramide De novo Synthesis in Colon Cancer Cells

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, CB 1 and CB 2 , in colorectal cancer and to provide new insight into the molecular pathways underlying the...

Full description

Saved in:

Bibliographic Details
Published in:	Clinical cancer research Vol. 14; no. 23; pp. 7691 - 7700
Main Authors:	CIANCHI, Fabio, PAPUCCI, Laura, DONNINI, Martino, PERIGLI, Giuliano, TRALLORI, Giacomo, TANGANELLI, Elisabetta, CAPACCIOLI, Sergio, MASINI, Emanuela, SCHIAVONE, Nicola, LULLI, Matteo, MAGNELLI, Lucia, CRISTINAVINCI, Maria, MESSERINI, Luca, MANERA, Clementina, RONCONI, Elisa, ROMAGNANI, Paola
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 01-12-2008
Subjects:	Animals Anticancéreux apoptosis Apoptosis - physiology Blotting, Western cannabinoids Cell Line, Tumor ceramide Ceramides - biosynthesis Colonic Neoplasms - metabolism colorectal cancer Enzyme-Linked Immunosorbent Assay Estomac. Duodénum. Intestin grêle. Côlon. Rectum. Anus Flow Cytometry Fluorescent Antibody Technique Gastroenterologie. Foie. Pancreas. Abdomen Humans Immunohistochemistry Mice Mice, Nude Pharmacologie. Traitements medicamenteux Receptor, Cannabinoid, CB1 - metabolism Receptor, Cannabinoid, CB2 - metabolism Reverse Transcriptase Polymerase Chain Reaction RNA, Small Interfering Sciences biologiques et medicales Sciences medicales TNF-α Transfection Tumeurs Tumor Necrosis Factor-alpha - metabolism Pathologie de l'intestin Régulation Tumeur maligne Sphingolipide Pathologie de l'appareil digestif Pathologie du côlon Activation Cancer du côlon De novo Cancer Céramide
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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, CB 1 and CB 2 , 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 CB 1 agonist arachinodyl-2'-chloroethylamide and the CB 2 agonist N -cyclopentyl-7-methyl-1-(2-morpholin-4-ylethyl)-1,8-naphthyridin-4(1 H )-on-3-carboxamide (CB13) on tumor cell apoptosis and ceramide and tumor necrosis factor (TNF)-α production were evaluated. The knockdown of TNF-α mRNA was obtained with the use of selective small interfering RNA. Results: We show that the CB 1 receptor was mainly expressed in human normal colonic epithelium whereas tumor tissue was strongly positive for the CB 2 receptor. The activation of the CB 1 and, more efficiently, of the CB 2 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-α mRNA abrogated the ceramide increase and, therefore, the apoptotic effect induced by cannabinoid receptor activation. Conclusions: The present study shows that either CB 1 or CB 2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells. Our data unveiled, for the first time, that TNF-α acts as a link between cannabinoid receptor activation and ceramide production.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1078-0432 1557-3265
DOI:	10.1158/1078-0432.CCR-08-0799