Blázquez Ortiz, CristinaSalazar Roa, MaríaArkaitz Carracedo, ArkaitzLorente Pérez, María Del MarEgia, AinaraGonzalez Feria, LuisHaro Ramos, Amador DeVelasco Díez, GuillermoGuzmán Pastor, Manuel2024-02-012024-02-012008Cristina Blázquez, María Salazar, Arkaitz Carracedo, Mar Lorente, Ainara Egia, Luis González-Feria, Amador Haro, Guillermo Velasco, Manuel Guzmán; Cannabinoids Inhibit Glioma Cell Invasion by Down-regulating Matrix Metalloproteinase-2 Expression. Cancer Res 15 March 2008; 68 (6): 1945–1952. https://doi.org/10.1158/0008-5472.CAN-07-51760008-547210.1158/0008-5472.CAN-07-5176https://hdl.handle.net/20.500.14352/97836Cannabinoids, the active components of Cannabis sativa L. and their derivatives, inhibit tumor growth in laboratory animals by inducing apoptosis of tumor cells and impairing tumor angiogenesis. It has also been reported that these compounds inhibit tumor cell spreading, but the molecular targets of this cannabinoid action remain elusive. Here, we evaluated the effect of cannabinoids on matrix metallopro- teinase (MMP) expression and its effect on tumor cell invasion. Local administration of #9-tetrahydrocannabinol (THC), the major active ingredient of cannabis, down- regulated MMP-2 expression in gliomas generated in mice, as determined by Western blot, immunofluorescence, and real-time quantitative PCR analyses. This cannabinoid- induced inhibition of MMP-2 expression in gliomas (a) was MMP-2–selective, as levels of other MMP family members were unaffected; (b) was mimicked by JWH-133, a CB2 cannabinoid receptor–selective agonist that is devoid of psychoactive side effects; (c) was abrogated by fumonisin B1, a selective inhibitor of ceramide biosynthesis; and (d) was also evident in two patients with recurrent glioblastoma multiforme. THC inhibited MMP-2 expression and cell invasion in cultured glioma cells. Manipulation of MMP-2 expression by RNA interference and cDNA overexpression experiments proved that down-regulation of this MMP plays a critical role in THC- mediated inhibition of cell invasion. Cannabinoid-induced inhibition of MMP-2 expression and cell invasion was prevented by blocking ceramide biosynthesis and by knock- ing-down the expression of the stress protein p8. As MMP-2 up-regulation is associated with high progression and poor prognosis of gliomas and many other tumors, MMP-2 down- regulation constitutes a new hallmark of cannabinoid anti- tumoral activity.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/journal article1538-7445https://doi.org/10.1158/0008-5472.CAN-07-5176open accessCannabinoids, GliomasBioquímica (Biología)2403 Bioquímica