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首页> 外文期刊>Cell cycle >Nutlin-3 inhibits the NFkappaB pathway in a p53-dependent manner: implications in lung cancer therapy.
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Nutlin-3 inhibits the NFkappaB pathway in a p53-dependent manner: implications in lung cancer therapy.

机译：Nutlin-3以p53依赖性方式抑制NFkappaB途径：在肺癌治疗中具有重要意义。

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Nutlins were identified as the first potent and specific small molecule Mdm2 antagonists that inhibit the p53-Mdm2 interaction. We show in this study that Nutlin-3 can downregulate TNFalpha induced activation of the NFkappaB reporter in lung cancer cells. Activation of p53 dependent transcription is not compromised when Nutlin-3 is combined with TNFalpha. Instead, this combination treatment decreases cell viability in a p53 dependent manner. We show that Nutlin-3 strikingly inhibits the protein expression of NFkappaB target genes ICAM-1 and MCP-1 while other targets like Bcl-xL and FLIP are not affected, thereby suggesting that the inhibition is promoter specific. This inhibition of ICAM-1 and MCP-1 by Nutlin-3 is again dependent on the p53 status in cells. Furthermore, we show that Nutlin-3 strongly inhibits protein expression of ICAM-1 and MCP-1 induced by IL1, another NFkappaB activating stimuli. Nutlin-3 does not inhibit Akt phosphorylation, IkappaB alpha phosphorylation, IkappaB alpha degradation,p65 modification or p65 DNA binding in the cell lines tested. This study suggests the potential of Nutlin-3 as a bitargeted anti-cancer drug by simultaneously causing p53 activation and NFkappaB suppression. It also suggests that Nutlin-3 could be evaluated for treatment of lung cancer as a single agent or in combination therapy by targeting its effect on ICAM-1 and MCP-1 which are known to be critical for cancer cell invasion, thereby downregulating tumor formation and metastasis. This study also suggests biomarkers of response for evaluation of Nutlin-3 in the clinic.
机译：坚果蛋白被认为是抑制p53-Mdm2相互作用的第一种有效的特异小分子Mdm2拮抗剂。我们在这项研究中显示，Nutlin-3可以下调TNFalpha诱导的肺癌细胞中NFkappaB报告基因的激活。当Nutlin-3与TNFalpha结合使用时，不会损害p53依赖性转录的激活。相反，这种联合治疗以p53依赖的方式降低细胞活力。我们显示，Nutlin-3显着抑制NFkappaB目标基因ICAM-1和MCP-1的蛋白质表达，而其他目标（如Bcl-xL和FLIP）不受影响，从而表明该抑制作用是启动子特异性的。 Nutlin-3对ICAM-1和MCP-1的这种抑制再次取决于细胞中p53的状态。此外，我们显示Nutlin-3强烈抑制由IL1（另一个激活NFkappaB的刺激物）诱导的ICAM-1和MCP-1的蛋白质表达。 Nutlin-3在测试的细胞系中不抑制Akt磷酸化，IkappaB alpha磷酸化，IkappaB alpha降解，p65修饰或p65 DNA结合。这项研究表明，Nutlin-3可能通过同时引起p53激活和NFkappB抑制而成为一种双靶抗癌药物。这也表明可以通过靶向Nutlin-3对ICAM-1和MCP-1的作用来评估肺癌的治疗效果，从而将其作为单一药物或联合疗法进行评估，众所周知，ICAM-1和MCP-1对癌细胞的侵袭至关重要，从而下调了肿瘤的形成和转移。这项研究还提出了在临床中评估Nutlin-3的反应生物标志物。

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