|
|
 What is RSS?
Published Online: 21 Jun 2007
Copyright © 2007 Wiley-Liss, Inc.
|
|
|
|
Cancer Cell Biology
The cannabinoid  9-tetrahydrocannabinol inhibits RAS-MAPK and PI3K-AKT survival signalling and induces BAD-mediated apoptosis in colorectal cancer cells
|
Alexander Greenhough, Helena A. Patsos, Ann C. Williams, Christos Paraskeva * |
Department of Cellular and Molecular Medicine, Cancer Research UK, Colorectal Tumour Biology Group, School of Medical Sciences, University of Bristol, University Walk, Bristol, United Kingdom
|
| email: Christos Paraskeva (c.paraskeva@bristol.ac.uk) |
*Correspondence to Christos Paraskeva, Department of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, UK
Fax: +44-117-928-7896.
Funded by:
 Cancer Research UK and the Citrina Foundation
| colorectal cancer • survival signalling • cannabinoid • apoptosis • BAD |
Deregulation of cell survival pathways and resistance to apoptosis are widely accepted to be fundamental aspects of tumorigenesis. As in many tumours, the aberrant growth and survival of colorectal tumour cells is dependent upon a small number of highly activated signalling pathways, the inhibition of which elicits potent growth inhibitory or apoptotic responses in tumour cells. Accordingly, there is considerable interest in therapeutics that can modulate survival signalling pathways and target cancer cells for death. There is emerging evidence that cannabinoids, especially  9-tetrahydrocannabinol (THC), may represent novel anticancer agents, due to their ability to regulate signalling pathways critical for cell growth and survival. Here, we report that CB1 and CB2 cannabinoid receptors are expressed in human colorectal adenoma and carcinoma cells, and show for the first time that THC induces apoptosis in colorectal cancer cells. THC-induced apoptosis was rescued by pharmacological blockade of the CB1, but not CB2, cannabinoid receptor. Importantly, THC treatment resulted in CB1-mediated inhibition of both RAS-MAPK/ERK and PI3K-AKT survival signalling cascades; two key cell survival pathways frequently deregulated in colorectal tumours. The inhibition of ERK and AKT activity by THC was accompanied by activation of the proapoptotic BCL-2 family member BAD. Reduction of BAD protein expression by RNA interference rescued colorectal cancer cells from THC-induced apoptosis. These data suggest an important role for CB1 receptors and BAD in the regulation of apoptosis in colorectal cancer cells. The use of THC, or selective targeting of the CB1 receptor, may represent a novel strategy for colorectal cancer therapy. © 2007 Wiley-Liss, Inc. |
Received: 22 November 2006; Accepted: 15 May 2007
|
|
Increased endocannabinoid levels reduce the development of precancerous lesions in the mouse colon
|
|
Angelo A. Izzo1  , Gabriella Aviello1, Stefania Petrosino2, 3, Pierangelo Orlando4, Giovanni Marsicano5, 6, 9, Beat Lutz5, 6, Francesca Borrelli1, Raffaele Capasso1, Santosh Nigam7, 8, Francesco Capasso1, Vincenzo Di Marzo2 and Endocannabinoid Research Group
| (1) |
Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy |
| (2) |
Institute of Biomolecular Chemistry, National Research Council, Pozzuoli (NA), Italy |
| (3) |
Department of Pharmaceutical Sciences, University of Salerno, Fisciano, Italy |
| (4) |
Institute of Protein Biochemistry, National Research Council, Naples, Italy |
| (5) |
Molecular Genetics of Behaviour, Max Planck Institute of Psychiatry, Munich, Germany |
| (6) |
Department of Physiological Chemistry, Johannes Gutenberg-University Mainz, Mainz, Germany |
| (7) |
Eicosanoid and Lipid Research Division, Centre for Experimental Gynecology and Breast Research, Free University Berlin, Berlin, Germany |
| (8) |
Centre for Experimental Gynecology and Breast Research, Free University Berlin, Berlin, Germany |
| (9) |
Present address: U 862 Centre de Recherche INSERM François Magendie, Equipe AVENIR 4, 146, rue Léo Saignat, 33077 Bordeaux, France |
Received: 18 April 2007 Revised: 6 July 2007 Accepted: 10 July 2007 Published online: 6 September 2007
Abstract Colorectal cancer is an increasingly important cause of death in Western countries. Endocannabinoids inhibit colorectal carcinoma cell proliferation in vitro. In this paper, we investigated the involvement of endocannabinoids on the formation of aberrant crypt foci (ACF, earliest preneoplastic lesions) in the colon mouse in vivo. ACF were induced by azoxymethane (AOM); fatty acid amide hydrolase (FAAH) and cannabinoid receptor messenger ribonucleic acid (mRNA) levels were analyzed by the quantitative reverse transcription polymerase chain reaction (RT-PCR); endocannabinoid levels were measured by liquid chromatography–mass spectrometry; caspase-3 and caspase-9 expressions were measured by Western blot analysis. Colonic ACF formation after AOM administration was associated with increased levels of 2-arachidonoylglycerol (with no changes in FAAH and cannabinoid receptor mRNA levels) and reduction in cleaved caspase-3 and caspase-9 expression. The FAAH inhibitor N-arachidonoylserotonin increased colon endocannabinoid levels, reduced ACF formation, and partially normalized cleaved caspase-3 (but not caspase-9) expression. Notably, N-arachidonoylserotonin completely prevented the formation of ACF with four or more crypts, which have been show to be best correlated with final tumor incidence. The effect of N-arachidonoylserotonin on ACF formation was mimicked by the cannabinoid receptor agonist HU-210. No differences in ACF formation were observed between CB1 receptor-deficient and wild-type mice. It is concluded that pharmacological enhancement of endocannabinoid levels (through inhibition of endocannabinoid hydrolysis) reduces the development of precancerous lesions in the mouse colon. The protective effect appears to involve caspase-3 (but not caspase-9) activation.
Keywords Aberrant crypt foci - 2-arachidonoylglycerol - Cannabinoid receptors - Colon cancer - Fatty acid amide hydrolase (FAAH)
Angelo A. Izzo and Gabriella Aviello equally contributed to this work.
Angelo A. Izzo, Gabriella Aviello, Stefania Petrosino, Pierangelo Orlando, Francesca Borrelli, Raffaele Capasso, Francesco Capasso, and Vincenzo Di Marzo are part of the Endocannabinoid Research Group.
|
|
