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首页> 外文期刊>Apoptosis >Mdm2 inhibition induces apoptosis in p53 deficient human colon cancer cells by activating p73- and E2F1-mediated expression of PUMA and Siva-1
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Mdm2 inhibition induces apoptosis in p53 deficient human colon cancer cells by activating p73- and E2F1-mediated expression of PUMA and Siva-1

机译：Mdm2抑制通过激活p73和E2F1介导的PUMA和Siva-1的表达诱导p53缺陷的人结肠癌细胞凋亡。

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摘要

Camptothecin (CPT) and Nutlin-3 caused apoptosis by increasing p53 protein and its activation in intestinal epithelial cells (IEC-6). We studied the effectiveness of these inducers on apoptosis in human colon cancer cells (Caco2) lacking p53 expression. CPT failed to activate caspase-3 and cause apoptosis in these cells. The absence of p53 expression, higher basal Bcl-xL and lower Bax proteins prevented CPT-induced apoptosis. However, the Mdm2 antagonist Nutlin-3 induced apoptosis in a dose dependent manner by activating caspases-9 and -3. Nutlin-3 prevented the activation of AKT via PTEN-mediated inhibition of the PI3K pathway. Nutlin-3 increased the phosphorylation of retinoblastoma protein causing E2F1 release leading to induction of Siva-1. Nutlin-3-mediated degradation of Mdm2 caused the accumulation of p73, which induced the expression of p53 up-regulated modulator of apoptosis (PUMA). E2F1 and p73 knockdown decreased the expression of Siva and PUMA, respectively and abolished Nutlin-3-induced caspase-3 activation. Cycloheximide (CHX) inhibited Nutlin-3-induced Siva, Noxa, and PUMA expression and inhibited apoptosis in IEC-6 and Caco2 cells. These results indicate that translation of mRNAs induced by Nutlin-3 is critical for apoptosis. In summary, apoptosis in Caco2 cells lacking functional p53 occurred following the disruption of Mdm2 binding with p73 and Rb leading to the expression of pro-apoptotic proteins, PUMA, Noxa, and Siva-1.
机译：喜树碱（CPT）和Nutlin-3通过增加p53蛋白及其在肠上皮细胞（IEC-6）中的活化而引起凋亡。我们研究了这些诱导剂对缺乏p53表达的人结肠癌细胞（Caco2）凋亡的有效性。 CPT未能激活caspase-3，并导致这些细胞凋亡。不存在p53表达，较高的基础Bcl-xL和较低的Bax蛋白可阻止CPT诱导的细胞凋亡。但是，Mdm2拮抗剂Nutlin-3通过激活caspases-9和-3以剂量依赖的方式诱导凋亡。 Nutlin-3通过PTEN介导的PI3K途径抑制作用阻止了AKT的激活。 Nutlin-3增加了视网膜母细胞瘤蛋白的磷酸化，导致E2F1释放，导致Siva-1的诱导。 Nutlin-3介导的Mdm2降解引起p73的积累，从而诱导p53的表达上调了凋亡调节因子（PUMA）。 E2F1和p73敲低分别降低了Siva和PUMA的表达，并废除了Nutlin-3诱导的caspase-3活化。环己酰亚胺（CHX）抑制Nutlin-3诱导的Siva，Noxa和PUMA表达，并抑制IEC-6和Caco2细胞的凋亡。这些结果表明，Nutlin-3诱导的mRNA的翻译对于细胞凋亡至关重要。总之，在缺乏功能性p53的Caco2细胞中，凋亡发生在Mdm2与p73和Rb的结合破坏后，导致促凋亡蛋白，PUMA，Noxa和Siva-1的表达。

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