JunD is involved in the antiproliferative effect of Δ9-tetrahydrocannabinol on human breast cancer cells
JunD is involved in the antiproliferative effect of Δ9-tetrahydrocannabinol on human breast cancer cells
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DOI：
10.1038/onc.2008.145
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发表时间：
2008-08-28
期刊：
影响因子：
8
通讯作者：
Sanchez, C.
中科院分区：
文献类型：
--
作者：
Caffarel, M. M.;Moreno-Bueno, G.;Sanchez, C.
最近有研究表明，大麻及其衍生物的活性成分大麻素可以抑制人类乳腺癌细胞的细胞周期进程。本文研究了δ(9)-四氢大麻酚（THC）在这些细胞中的抗增殖作用机制，并表明其与AP-1转录因子家族成员JunD的调节有关。THC通过上调基因表达和将蛋白转运到核室来激活JunD，这些事件伴随着细胞增殖的减少。有趣的是，在暴露于四氢大麻酚的人类非肿瘤乳腺上皮细胞中，没有观察到JunD激活或增殖抑制。我们通过RNA干扰和基因消融证实了JunD在THC作用中的重要性。因此，在JunD沉默的人乳腺癌细胞和JunD敲除小鼠中衍生的永生化。四氢大麻酚的抗增殖作用明显减弱。基因阵列和siRNA实验支持周期蛋白依赖性激酶抑制剂p27和肿瘤抑制基因测试是大麻素作用中JunD的候选靶点。此外，我们的数据表明，应激调节蛋白p8以不依赖于jun的方式参与THC的抗增殖作用。总而言之，这是第一份不仅表明大麻素调节JunD，而且更普遍地说，JunD的激活减少了癌细胞的增殖，这指出了抑制乳腺癌进展的新靶点。
It has been recently shown that cannabinoids, the active components of marijuana and their derivatives, inhibit cell cycle progression of human breast cancer cells. Here we studied the mechanism of Delta(9)-tetrahydrocannabinol (THC) antiproliferative action in these cells, and show that it involves the modulation of JunD, a member of the AP-1 transcription factor family. THC activates JunD both by upregulating gene expression and by translocating the protein to the nuclear compartment, and these events are accompanied by a decrease in cell proliferation. Of interest, neither JunD activation nor proliferation inhibition was observed in human non-tumour mammary epithelial cells exposed to THC. We confirmed the importance of JunD in THC action by RNA interference and genetic ablation. Thus, in both JunD-silenced human breast cancer cells and JunD knockout mice-derived immortalized. broblasts, the antiproliferative effect exerted by THC was significantly diminished. Gene array and siRNA experiments support that the cyclin-dependent kinase inhibitor p27 and the tumour suppressor gene testin are candidate JunD targets in cannabinoid action. In addition, our data suggest that the stress-regulated protein p8 participates in THC antiproliferative action in a JunD-independent manner. In summary, this is the first report showing not only that cannabinoids regulate JunD but, more generally, that JunD activation reduces the proliferation of cancer cells, which points to a new target to inhibit breast cancer progression.