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锌（II）-姜黄素作用于甲状腺癌细胞中的p53。

Zn(II)-curc targets p53 in thyroid cancer cells.

作者信息

Garufi Alessia, D'Orazi Valerio, Crispini Alessandra, D'Orazi Gabriella

机构信息

Department of Experimental Oncology, Regina Elena National Cancer Institute, Rome, Italy.

Department of Surgical Sciences, Sapienza University, Rome, Italy.

出版信息

Int J Oncol. 2015 Oct;47(4):1241-8. doi: 10.3892/ijo.2015.3125. Epub 2015 Aug 13.

DOI:10.3892/ijo.2015.3125
PMID:26314369
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4583539/
Abstract

TP53 mutation is a common event in many cancers, including thyroid carcinoma. Defective p53 activity promotes cancer resistance to therapies and a more malignant phenotype, acquiring oncogenic functions. Rescuing the function of mutant p53 (mutp53) protein is an attractive anticancer therapeutic strategy. Zn(II)-curc is a novel small molecule that has been shown to target mutp53 protein in several cancer cells, but its effect in thyroid cancer cells remains unclear. Here, we investigated whether Zn(II)-curc could affect p53 in thyroid cancer cells with both p53 mutation (R273H) and wild-type p53. Zn(II)-curc induced mutp53H273 downregulation and reactivation of wild-type functions, such as binding to canonical target promoters and target gene transactivation. This latter effect was similar to that induced by PRIMA-1. In addition, Zn(II)-curc triggered p53 target gene expression in wild-type p53-carrying cells. In combination treatments, Zn(II)-curc enhanced the antitumor activity of chemotherapeutic drugs, in both mutant and wild-type-carrying cancer cells. Taken together, our data indicate that Zn(II)-curc promotes the reactivation of p53 in thyroid cancer cells, providing in vitro evidence for a potential therapeutic approach in thyroid cancers.

摘要

TP53突变在包括甲状腺癌在内的许多癌症中是常见事件。p53活性缺陷会促进癌症对治疗的抗性以及更恶性的表型，获得致癌功能。挽救突变型p53（mutp53）蛋白的功能是一种有吸引力的抗癌治疗策略。Zn（II）-姜黄素是一种新型小分子，已显示在几种癌细胞中靶向mutp53蛋白，但其在甲状腺癌细胞中的作用仍不清楚。在这里，我们研究了Zn（II）-姜黄素是否会影响具有p53突变（R273H）和野生型p53的甲状腺癌细胞中的p53。Zn（II）-姜黄素诱导mutp53H273下调并重新激活野生型功能，如与典型靶启动子结合和靶基因反式激活。后一种效应与PRIMA-1诱导的效应相似。此外，Zn（II）-姜黄素在携带野生型p53的细胞中触发p53靶基因表达。在联合治疗中，Zn（II）-姜黄素增强了化疗药物在突变型和携带野生型的癌细胞中的抗肿瘤活性。综上所述，我们的数据表明Zn（II）-姜黄素促进甲状腺癌细胞中p53的重新激活，为甲状腺癌的潜在治疗方法提供了体外证据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c75/4583539/20d22edc8c69/IJO-47-04-1241-g04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c75/4583539/017a1451351b/IJO-47-04-1241-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c75/4583539/5e90de02f966/IJO-47-04-1241-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c75/4583539/f42b4ccf6f0f/IJO-47-04-1241-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c75/4583539/699efa51a46c/IJO-47-04-1241-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c75/4583539/20d22edc8c69/IJO-47-04-1241-g04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c75/4583539/017a1451351b/IJO-47-04-1241-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c75/4583539/5e90de02f966/IJO-47-04-1241-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c75/4583539/f42b4ccf6f0f/IJO-47-04-1241-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c75/4583539/699efa51a46c/IJO-47-04-1241-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0c75/4583539/20d22edc8c69/IJO-47-04-1241-g04.jpg

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本文引用的文献

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Synthetic metallochaperone ZMC1 rescues mutant p53 conformation by transporting zinc into cells as an ionophore.合成金属伴侣ZMC1作为离子载体将锌转运到细胞中，从而挽救突变型p53的构象。
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Pharmacological reactivation of p53 as a strategy to treat cancer.作为治疗癌症的策略，药理学激活 p53。
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