Triptolide inhibits MDM2 and induces apoptosis in acute lymphoblastic leukemia cells through a p53-independent pathway.
Triptolide inhibits MDM2 and induces apoptosis in acute lymphoblastic leukemia cells through a p53-independent pathway.
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DOI：
10.1158/1535-7163.mct-12-0425
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发表时间：
2013-02
影响因子：
5.7
通讯作者：
Zhou M
中科院分区：
文献类型：
--
作者：
Huang M;Zhang H;Liu T;Tian D;Gu L;Zhou M
雷公藤甲素是一种从中国植物雷公藤中提取的天然产物，据报道，它在多种癌症中具有抗肿瘤作用。雷公藤甲素的抗肿瘤活性与其生物学活性有关，因为它抑制多种促增殖或抗凋亡因子，这些因子主要在特定类型的癌细胞中表达。在此，我们证明了雷公藤甲素通过抑制MDM2的表达，诱导了MDM2癌蛋白高表达的急性淋巴细胞白血病(ALL)细胞亚群的凋亡。更具体地说，我们发现雷公藤甲素通过抑制MDM2的mRNA合成在转录水平上抑制了MDM2。这种MDM2抑制转而导致P53蛋白水平的增加；然而，由于雷公藤内酯醇处理的细胞缺乏p21和PUMA的诱导以及在G1期细胞周期停滞的事实，P53功能没有被激活。雷公藤甲素介导的MDM2下调增加了其翻译靶点XIAP的抑制，其方式不同于对细胞应激和DNA损伤剂电离辐射(IR)的反应，后者因P53激活的MDM2而导致XIAP。这些结果表明，由于MDM2下调对XIAP的抑制程度增加，可能在雷公藤甲素诱导MDM2高表达肿瘤细胞凋亡的过程中发挥关键作用。
Triptolide, a natural product derived from the Chinese plant Tripterygium wilfordii, is reported to exhibit antitumor effects in a broad range of cancers. The antitumor activity of triptolide is associated with its biological activities, as it inhibits various pro-proliferative or anti-apoptotic factors that are dominantly expressed in given types of cancer cells. Herein, we demonstrate that triptolide induced apoptosis in a subgroup of acute lymphoblastic leukemia (ALL) cells overexpressing the MDM2 oncoprotein, by inhibiting MDM2 expression. More specifically, we found that triptolide inhibited MDM2 at the transcriptional level by suppressing its mRNA synthesis. This MDM2 inhibition led in turn to increased levels of p53 protein; however, p53 functionality was not activated, due to the fact that triptolide-treated cells lacked induction of p21 and PUMA as well as in G1 cell-cycle arrest. Triptolide-mediated downregulation of MDM2 increased inhibition of XIAP, its translational target, in a manner distinct from reactions to cellular stress and DNA-damaging agent ionizing radiation (IR) that induce XIAP due to p53-activated MDM2. These results suggest that increased inhibition of XIAP due to downregulation of MDM2 may play a critical role in triptolide-induced apoptosis in MDM2-overexpressing cancers.