Originally published In Press as doi:10.1074/jbc.M608900200 on January 2, 2007
J. Biol. Chem., Vol. 282, Issue 9, 6854-6862, March 2, 2007
Cannabinoids Induce Glioma Stem-like Cell Differentiation and Inhibit Gliomagenesis*
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3From 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.