HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 9, 6854-6862, March 2, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/9/6854    most recent M608900200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Aguado, T. Articles by Galve-Roperh, I. Search for Related Content PubMed PubMed Citation Articles by Aguado, T. Articles by Galve-Roperh, I. Social Bookmarking                      What's this?

Cannabinoids Induce Glioma Stem-like Cell Differentiation and Inhibit Gliomagenesis^*

Tania Aguado¹, Arkaitz Carracedo, Boris Julien², Guillermo Velasco, Garry Milman, Raphael Mechoulam, Luis Alvarez^¶, Manuel Guzmán, and Ismael Galve-Roperh³

From the Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040 Madrid, Spain, the Department of Medicinal Chemistry and Natural Products, School of Pharmacy, Hebrew University, 91120 Jerusalem, Israel, and the ^¶Research Unit, La Paz University Hospital, 28046 Madrid, Spain

Glioma stem-like cells constitute one of the potential origins of gliomas, and therefore, their elimination is an essential factor for the development of efficient therapeutic strategies. Cannabinoids are known to exert an antitumoral action on gliomas that relies on at least two mechanisms: induction of apoptosis of transformed cells and inhibition of tumor angiogenesis. However, whether cannabinoids target human glioma stem cells and their potential impact in gliomagenesis are unknown. Here, we show that glioma stem-like cells derived from glioblastoma multiforme biopsies and the glioma cell lines U87MG and U373MG express cannabinoid type 1 (CB₁) and type 2 (CB₂) receptors and other elements of the endocannabinoid system. In gene array experiments, CB receptor activation altered the expression of genes involved in the regulation of stem cell proliferation and differentiation. The cannabinoid agonists HU-210 and JWH-133 promoted glial differentiation in a CB receptor-dependent manner as shown by the increased number of S-100- and glial fibrillary acidic protein-expressing cells. In parallel, cannabinoids decreased the cell population expressing the neuroepithelial progenitor marker nestin. Moreover, cannabinoid challenge decreased the efficiency of glioma stem-like cells to initiate glioma formation in vivo, a finding that correlated with decreased neurosphere formation and cell proliferation in secondary xenografts. Gliomas derived from cannabinoid-treated cancer stem-like cells were characterized with a panel of neural markers and evidenced a more differentiated phenotype and a concomitant decrease in nestin expression. Overall, our results demonstrate that cannabinoids target glioma stem-like cells, promote their differentiation, and inhibit gliomagenesis, thus giving further support to their potential use in the management of malignant gliomas.

Received for publication, September 18, 2006 , and in revised form, December 19, 2006.

^* This work was supported in part by Ministerio de Educación y Ciencia Grant SAF2006-00918, Santander/Universidad Complutense Madrid Grant PR27/05-13988, Comunidad Autónoma de Madrid Grants GR/SAL589-04 and S-SAL/0261/2006, and the Fundación Científica de la Asociación Española Contra el Cáncer. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2 and Table 1.

¹ Supported by the Comunidad Autónoma de Madrid.

² Supported by a postdoctoral fellowship from the Association pour la Recherche sur le Cancer (France).

³ Supported by the Ramón y Cajal Program of the Ministerio de Educación y Ciencia. To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology I, School of Biology, Complutense University, c/José Antonio Novais s/n, 28040 Madrid, Spain. Tel.: 34-91-394-4668; Fax: 34-91-394-4672; E-mail: igr{at}quim.ucm.es.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?