Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression
Cannabinoids inhibit glioma cell invasion by down-regulating matrix metalloproteinase-2 expression
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DOI：
10.1158/0008-5472.can-07-5176
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发表时间：
2008-03-15
期刊：
影响因子：
11.2
通讯作者：
Guzman, Manuel
中科院分区：
文献类型：
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作者：
Blazquez, Cristina;Salazar, Maria;Guzman, Manuel
大麻素是大麻的活性成分。和它们的衍生物，通过诱导肿瘤细胞凋亡和损害肿瘤血管生成来抑制实验动物中的肿瘤生长。据报道，这些化合物抑制肿瘤细胞扩散，但这种大麻素作用的分子靶点仍然难以捉摸。在这里，我们评估了大麻素对基质金属蛋白酶（MMP）表达的影响及其对肿瘤细胞侵袭的影响。通过Western印迹、免疫荧光、实时定量PCR分析确定，大麻的主要活性成分Delta（9）-四氢大麻酚（THC）的局部给药下调小鼠中产生的胶质瘤中MMP-2的表达。这种大麻素诱导的胶质瘤中MMP-2表达的抑制（a）是MMP-2选择性的，因为其他MMP家族成员的水平不受影响;（B）被JWH-133模仿，JWH-133是一种CB 2大麻素受体选择性激动剂，没有精神副作用;（c）被伏马菌素B1废除，伏马菌素B1是一种神经酰胺生物合成的选择性抑制剂;和（d）在两个复发性多形性胶质母细胞瘤患者中也是明显的。THC抑制胶质瘤细胞MMP-2表达和细胞侵袭。通过RNA干扰和cDNA过表达实验对MMP-2表达的操纵证明，该MMP的下调在THC介导的细胞侵袭抑制中起关键作用。大麻素诱导的MMP-2表达和细胞侵袭的抑制被阻止通过阻断神经酰胺的生物合成和通过敲低应激蛋白p8的表达。由于MMP-2上调与神经胶质瘤和许多其他肿瘤的高进展和不良预后相关，MMP-2下调构成大麻素抗肿瘤活性的新标志。
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, downregulated MMP-2 expression in gliomas generated in mice as determined by Western blot, immunofluorescence, an 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 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 downregulation constitutes a new hallmark of cannabinoid antitumoral activity.