Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression.
Cannabinoids, 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 metalloproteinase (MMP) expression and its effect on tumor cell invasion. Local administration of Delta(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 CB(2) 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 knocking-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 antitumoral activity.
Blázquez
Cristina
C
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain.
Salazar
María
M
Carracedo
Arkaitz
A
Lorente
Mar
M
Egia
Ainara
A
González-Feria
Luis
L
Haro
Amador
A
Velasco
Guillermo
G
Guzmán
Manuel
M
D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002518:Ceramides / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects; D013759:Dronabinol / Q000494:pharmacology; D037341:Fumonisins / Q000494:pharmacology; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D009361:Neoplasm Invasiveness; D051381:Rats; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists
D002186:Cannabinoids; D002518:Ceramides; D037341:Fumonisins; D061965:Matrix Metalloproteinase Inhibitors; D043885:Receptor, Cannabinoid, CB2; C056933:fumonisin B1; D013759:Dronabinol; D020778:Matrix Metalloproteinase 2; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC