Ursolic acid simultaneously targets multiple signaling pathways to suppress proliferation and induce apoptosis in colon cancer cells.
Ursolic acid simultaneously targets multiple signaling pathways to suppress proliferation and induce apoptosis in colon cancer cells.
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熊果酸同时靶向多种信号通路，抑制结肠癌细胞增殖并诱导细胞凋亡
DOI：
10.1371/journal.pone.0063872
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Deng W
中科院分区：
文献类型：
--
作者：
Wang J;Liu L;Qiu H;Zhang X;Guo W;Chen W;Tian Y;Fu L;Shi D;Cheng J;Huang W;Deng W
熊果酸（Ursolic acid，UA）是一种天然的五环三萜羧酸类化合物，具有抗肿瘤作用，是一种很有前途的抗癌药物，但其对结肠癌细胞的作用机制尚不清楚。在这里，我们确定了UA抑制细胞增殖和诱导人结肠癌SW 480和LoVo细胞凋亡的分子机制。UA处理导致细胞活力和克隆形成的显着抑制以及细胞形态和扩散的变化。UA还通过抑制MMP 9和上调CDH 1表达来抑制结肠癌细胞的迁移。进一步的研究表明UA抑制Akt和ERK蛋白的磷酸化。用Akt或ERK特异性抑制剂预处理可显著消除UA的增殖抑制作用。UA对结肠癌细胞考克斯-2表达和PGE 2的产生也有明显的抑制作用。用考克斯-2抑制剂（塞来昔布）预处理可消除UA诱导的细胞增殖。此外，我们发现UA能有效促进NF-κB和p300从细胞核向细胞质的移位，并减弱p300介导的NF-κB和CREB 2的乙酰化。用p300抑制剂（roscovitine）预处理废除了UA诱导的细胞增殖，这被p300过表达逆转。此外，UA处理诱导结肠癌细胞凋亡，增加PARP、caspase-3和9的裂解，抑制细胞色素c从线粒体膜间隙释放到胞浆中。这些结果表明UA通过同时调节MMP 9/CDH 1、Akt/ERK、考克斯-2/PGE 2、p300/NF-κB/CREB 2和细胞色素c/caspase等多条信号通路抑制结肠癌细胞增殖并诱导其凋亡。
Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid distributed in medical herbs, exerts antitumor effects and is emerging as a promising compound for cancer prevention and therapy, but its excise mechanisms of action in colon cancer cells remains largely unknown. Here, we identified the molecular mechanisms by which UA inhibited cell proliferation and induced apoptosis in human colon cancer SW480 and LoVo cells. Treatment with UA led to significant inhibitions in cell viability and clone formation and changes in cell morphology and spreading. UA also suppressed colon cancer cell migration by inhibiting MMP9 and upregulating CDH1 expression. Further studies showed that UA inhibited the phosphorylation of Akt and ERK proteins. Pretreatment with an Akt or ERK-specific inhibitor considerably abrogated the proliferation inhibition by UA. UA also significantly inhibited colon cancer cell COX-2 expression and PGE2 production. Pretreatment with a COX-2 inhibitor (celecoxib) abrogated the UA-induced cell proliferation. Moreover, we found that UA effectively promoted NF-κB and p300 translocation from cell nuclei to cytoplasm, and attenuated the p300-mediated acetylation of NF-κB and CREB2. Pretreatment with a p300 inhibitor (roscovitine) abrogated the UA-induced cell proliferation, which is reversed by p300 overexpression. Furthermore, UA treatment induced colon cancer cell apoptosis, increased the cleavage of PARP, caspase-3 and 9, and trigged the release of cytochrome c from mitochondrial inter-membrane space into cytosol. These results indicate that UA inhibits cell proliferation and induces apoptosis in colon cancer cells through simultaneous modulation of the multiple signaling pathways such as MMP9/CDH1, Akt/ERK, COX-2/PGE2, p300/NF-κB/CREB2, and cytochrome c/caspase pathways.
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DOI：
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发表时间：
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期刊：
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