Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
J Invest Dermatol. 2012 Feb;132(2):356-64. doi: 10.1038/jid.2011.313. Epub 2011 Oct 13.
Oncogenesis reflects an orchestrated interaction between misguided growth signals. Although much effort has been launched to pharmacologically disable activated oncogenes, one sidelined approach is the restoration of tumor suppressive signals. As TP53 is often structurally preserved, but functionally crippled, by CDKN2A/ARF loss in melanoma, rescue of p53 function represents an attractive point of vulnerability in melanoma. In this study, we showed that both p53 protein and activity levels in melanoma cells were strongly induced by nutlin-3, a canonical HDM2 antagonist. Among a test panel of 51 cell lines, there was a marked reduction in melanoma viability that was directly linked to TP53 status. Moreover, we also found that the melanoma growth suppression mediated by mitogen-activated protein kinase/extracellular signal-regulated kinase inhibition was potentiated by HDM2 antagonism. These results provide fundamental insights into the intact p53 circuitry, which can be restored through small molecule inhibitors and potentially deployed for therapeutic gain.
肿瘤发生反映了误导性生长信号之间的协调相互作用。尽管已经付出了很大的努力来通过药理学手段使激活的致癌基因失活，但一种被忽视的方法是恢复肿瘤抑制信号。由于黑色素瘤中 CDKN2A/ARF 的缺失常常使 TP53 在结构上得以保存，但在功能上却受到了损害，因此恢复 p53 功能代表了黑色素瘤中一个有吸引力的脆弱点。在这项研究中，我们表明，在黑色素瘤细胞中，nutlin-3（一种典型的 HDM2 拮抗剂）可强烈诱导 p53 蛋白和活性水平。在 51 个细胞系的测试面板中，黑色素瘤活力明显降低，这与 TP53 状态直接相关。此外，我们还发现，通过丝裂原活化蛋白激酶/细胞外信号调节激酶抑制介导的黑色素瘤生长抑制作用可以通过 HDM2 拮抗作用增强。这些结果为完整的 p53 电路提供了基本的见解，该电路可以通过小分子抑制剂恢复，并可能用于治疗获益。
