一种设计的p53聚集抑制剂可挽救卵巢癌中的p53肿瘤抑制功能。
A Designed Inhibitor of p53 Aggregation Rescues p53 Tumor Suppression in Ovarian Carcinomas.
作者信息
Soragni Alice, Janzen Deanna M, Johnson Lisa M, Lindgren Anne G, Thai-Quynh Nguyen Anh, Tiourin Ekaterina, Soriaga Angela B, Lu Jing, Jiang Lin, Faull Kym F, Pellegrini Matteo, Memarzadeh Sanaz, Eisenberg David S
机构信息
Departments of Biological Chemistry and Chemistry and Biochemistry, UCLA-DOE Institute, HHMI, 611 South Charles E. Young Drive, Los Angeles, CA 90095-1570, USA.
Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
出版信息
Cancer Cell. 2016 Jan 11;29(1):90-103. doi: 10.1016/j.ccell.2015.12.002. Epub 2015 Dec 31.
Half of all human cancers lose p53 function by missense mutations, with an unknown fraction of these containing p53 in a self-aggregated amyloid-like state. Here we show that a cell-penetrating peptide, ReACp53, designed to inhibit p53 amyloid formation, rescues p53 function in cancer cell lines and in organoids derived from high-grade serous ovarian carcinomas (HGSOC), an aggressive cancer characterized by ubiquitous p53 mutations. Rescued p53 behaves similarly to its wild-type counterpart in regulating target genes, reducing cell proliferation and increasing cell death. Intraperitoneal administration decreases tumor proliferation and shrinks xenografts in vivo. Our data show the effectiveness of targeting a specific aggregation defect of p53 and its potential applicability to HGSOCs.
在所有人类癌症中，有一半通过错义突变丧失p53功能，其中一部分p53处于自我聚集的淀粉样状态，比例未知。在此，我们表明，一种设计用于抑制p53淀粉样蛋白形成的细胞穿透肽ReACp53，可挽救癌细胞系以及源自高级别浆液性卵巢癌（HGSOC）的类器官中的p53功能，HGSOC是一种侵袭性癌症，其特征是普遍存在p53突变。挽救后的p53在调节靶基因、减少细胞增殖和增加细胞死亡方面的表现与其野生型对应物相似。腹腔注射可降低体内肿瘤增殖并缩小异种移植瘤。我们的数据表明，针对p53的特定聚集缺陷具有有效性，并且其在HGSOC中的潜在适用性。
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