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首页> 外文期刊>The Journal of investigative dermatology. >MDM2 inhibitor nutlin-3a induces apoptosis and senescence in cutaneous T-cell lymphoma: Role of p53
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MDM2 inhibitor nutlin-3a induces apoptosis and senescence in cutaneous T-cell lymphoma: Role of p53

机译：MDM2抑制剂nutlin-3a诱导皮肤T细胞淋巴瘤的凋亡和衰老：p53的作用

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P53 is rarely mutated in cutaneous T-cell lymphoma (CTCL) and is therefore a promising target for innovative therapeutic approaches. Nutlin-3a is an inhibitor of MDM2 (human homolog of murine double minute 2), which disrupts its interaction with p53, leading to the stabilization and activation of p53. To investigate the potential therapeutic use of nutlin-3a in CTCL, we screened CTCL lines Hut-78, SeAx, MyLa2000, Mac1, and Mac2a by measuring p53 levels after nutlin-3a treatment. In MyLa2000, Mac1, and Mac2a, we observed the increase in p53, indicating the fully functional p53. In the remaining cell lines, P53 mutation analysis identified a homozygous nonsense mutation (R196Stop in Hut-78) and a homozygous missense mutation (G245S in SeAx). In MyLa2000, Mac1, and Mac2a carrying wild-type P53, nutlin-3a induced apoptosis and senescence demonstrated by permanent G0/G1 cell-cycle block and expression of the senescence-associated Β-galactosidase. This effect was abolished in cells in which p53 was silenced by small interfering RNA. Sézary cells lack functional p53 and were resistant to nutlin-3a. However, nutlin-3a potentiated the efficacy of conventional chemotherapeutics not only in cells with intact p53 but also in Hut-78, SeAx, and Sézary cells. Thus, targeting p53 by nutlin-3a may constitute a therapeutic approach in CTCL because of increased apoptosis and senescence of tumor cells.
机译：P53在皮肤T细胞淋巴瘤（CTCL）中很少发生突变，因此是创新治疗方法的有希望的靶标。 Nutlin-3a是MDM2（鼠双分钟2的人类同源物）抑制剂，可破坏其与p53的相互作用，从而导致p53的稳定和活化。为了研究nutlin-3a在CTCL中的潜在治疗用途，我们通过测量nutlin-3a治疗后的p53水平来筛选CTCL系Hut-78，SeAx，MyLa2000，Mac1和Mac2a。在MyLa2000，Mac1和Mac2a中，我们观察到p53的增加，表明p53的功能全面。在剩余的细胞系中，P53突变分析确定了纯合的无义突变（Hut-78中的R196Stop）和纯合的错义突变（SeAx中的G245S）。在带有野生型P53的MyLa2000，Mac1和Mac2a中，nutlin-3a诱导了细胞凋亡和衰老，表现为永久性的G0 / G1细胞周期阻滞和衰老相关的β-半乳糖苷酶的表达。在p53被小的干扰RNA沉默的细胞中，这种作用被消除了。 Sézary细胞缺乏功能性p53，并且对nutlin-3a具有抗性。但是，nutlin-3a不仅在完整的p53细胞中而且在Hut-78，SeAx和Sézary细胞中增强了常规化学疗法的功效。因此，由于肿瘤细胞的凋亡和衰老增加，nutlin-3a靶向p53可能构成CTCL的治疗方法。

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