The PI3K/mTOR dual inhibitor NVP-BEZ235 stimulates mutant p53 degradation to exert anti-tumor effects on triple-negative breast cancer cells
The PI3K/mTOR dual inhibitor NVP-BEZ235 stimulates mutant p53 degradation to exert anti-tumor effects on triple-negative breast cancer cells
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DOI：
10.1002/2211-5463.12806
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发表时间：
2020-04-01
期刊：
影响因子：
2.6
通讯作者：
Guo, Xiaolan
中科院分区：
文献类型：
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作者：
Cai, Jiajing;Xia, Jingruo;Guo, Xiaolan
近一半的人类癌症含有p53突变，突变型p53（mutp 53）促进癌发生、转移、肿瘤复发和化疗耐药性。在30%的乳腺癌中观察到mutp 53，包括三阴性乳腺癌（TNBC），因此mutp 53是治疗TNBC的有希望的靶标。在这项研究中，我们研究了磷脂酰肌醇3激酶/哺乳动物雷帕霉素靶点双重抑制剂NVP-BEZ 235（BEZ 235）对两种具有mutp 53的TNBC细胞系：MDA-MB-231和MDA-MB-468的影响。通过3-（4，5-二甲基噻唑-2-基）-2，5-二苯基四氮唑溴化物、划痕实验、transwell和软琼脂实验检测细胞生长、迁移和集落形成能力，结果显示BEZ 235对TNBC细胞的生长、迁移和集落形成能力具有抑制作用。此外，BEZ 235引起这些细胞中mutp 53的降解。我们通过使用MG 132抑制蛋白酶体功能和使用3-甲基腺嘌呤和shRNA抑制自噬来研究潜在的机制。我们观察到BEZ 235可能通过抑制Akt/哺乳动物雷帕霉素靶点信号通路诱导自噬。通过敲低ATG 5和ATG 7进一步检查了观察到的TNBC细胞中mutp 53和自噬之间的相互作用，揭示了由BEZ 235诱导的mutp 53的降解可能不依赖于泛素-蛋白酶体途径和由ATG 5和ATG 7介导的自噬。此外，我们在TNBC细胞中发现了mutp 53和自噬之间正反馈的证据。总之，BEZ 235可能通过靶向mutp 53对TNBC细胞发挥抗肿瘤作用，这可能对未来疗法的开发具有意义。
Nearly half of human cancers harbor p53 mutations, and mutant p53 (mutp53) promotes carcinogenesis, metastasis, tumor recurrence and chemoresistance. mutp53 is observed in 30% of breast carcinomas, including triple-negative breast cancer (TNBC), and thus mutp53 is a promising target for treatment of TNBC. In this study, we investigated the effect of a phosphatidylinositide 3 kinase/mammalian target of rapamycin dual inhibitor, NVP-BEZ235 (BEZ235), on two TNBC cell lines with mutp53: MDA-MB-231 and MDA-MB-468. Cell growth, migration and colony-formation abilities were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide, scratch assay, transwell and soft agar assay, revealing that BEZ235 can inhibit the growth, migration and colony-formation abilities of TNBC cells. In addition, BEZ235 caused degradation of mutp53 in these cells. We investigated the underlying mechanism by inhibiting proteasome function using MG132 and inhibiting autophagy using 3-methyladenine and shRNAs. We observed that BEZ235 may induce autophagy through repression of the Akt/mammalian target of rapamycin signaling pathway. The observed interplay between mutp53 and autophagy in TNBC cells was examined further by knockdown of ATG5 and ATG7, revealing that degradation of mutp53 induced by BEZ235 may be independent of the ubiquitin-proteasome pathway and autophagy mediated by ATG5 and ATG7. Moreover, we found evidence of positive feedback between mutp53 and autophagy in TNBC cells. In conclusion, BEZ235 may exert antitumor effects against TNBC cells by targeting mutp53, and this may have implications for the development of future therapies.