Combination of a p53-activating CP-31398 and an MDM2 or a FAK inhibitor produces growth suppressive effects in mesothelioma with wild-type p53 genotype
Combination of a p53-activating CP-31398 and an MDM2 or a FAK inhibitor produces growth suppressive effects in mesothelioma with wild-type p53 genotype
复制标题
p53 激活 CP-31398 与 MDM2 或 FAK 抑制剂的组合可对野生型 p53 基因型间皮瘤产生生长抑制作用
DOI：
10.1007/s10495-020-01612-6
复制
发表时间：
2020
期刊：
影响因子：
7.2
通讯作者：
M. Tagawa
中科院分区：
文献类型：
--
作者：
Boya Zhong;M. Shingyoji;Michiko Hanazono;T. Nguyễn;T. Morinaga;Y. Tada;H. Shimada;K. Hiroshima;M. Tagawa
大多数间皮瘤具有野生型p53基因型，但主要由于INK 4A/ARF区域的遗传缺陷而导致p53功能缺陷。我们检查了CP-31398的生长抑制活性，其被开发用于恢复p53功能，而不管间皮瘤中野生型或突变型p53的基因型如何。CP-31398在具有野生型p53基因型的细胞中上调p53水平，但以不依赖于p53的方式诱导细胞生长抑制。相比之下，nutlin-3a，一种MDM 2抑制剂，增加了野生型p53基因型间皮瘤中的p53和p21水平，并产生了生长抑制作用。我们研究了CP-31398和nutlin-2a的组合作用，发现该组合在间皮瘤中与野生型p53产生协同生长抑制，但与突变型p53不产生协同生长抑制。蛋白质印迹分析表明，该组合增加p53和磷酸化水平大于用单一药剂的处理，增强PARP和半胱天冬酶-3的裂解，并降低磷酸化FAK水平。CP-31398和defactinib（一种FAK抑制剂）的组合也实现了协同抑制作用，并使p53与FAK去磷酸化水平高于单一治疗。这些数据表明，p53激活CP-31398与MDM 2或FAK抑制剂组合实现生长抑制作用，并提示p53升高和FAK失活之间可能存在相互作用途径。
A majority of mesothelioma had the wild-type p53 genotype but was defective of p53 functions primarily due to a genetic defect in INK4A/ARF region. We examined a growth suppressive activity of CP-31398 which was developed to restore the p53 functions irrespective of the genotype in mesothelioma with wild-type or mutated p53. CP-31398 up-regulated p53 levels in cells with wild-type p53 genotype but induced cell growth suppression in a p53-independent manner. In contrasts, nutlin-3a, an MDM2 inhibitor, increased p53 and p21 levels in mesothelioma with the wild-type p53 genotype and produced growth suppressive effects. We investigated a combinatory effect of CP-31398 and nutlin-2a and found the combination produced synergistic growth inhibition in mesothelioma with the wild-type p53 but not with mutated p53. Western blot analysis showed that the combination increased p53 and the phosphorylation levels greater than treatments with the single agent, augmented cleavages of PARP and caspase-3, and decreased phosphorylated FAK levels. Combination of CP-31398 and defactinib, a FAK inhibitor, also achieved synergistic inhibitory effects and increased p53 with FAK dephosphorylation levels greater than the single treatment. These data indicated that a p53-activating CP-31398 achieved growth inhibitory effects in combination with a MDM2 or a FAK inhibitor and suggested a possible reciprocal pathway between p53 elevation and FAK inactivation.
影响因子：
16
作者：
Lim, Ssang-Taek;Chen, Xiao Lei;Llic, Dusko
通讯作者：
Llic, Dusko