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The PI3K/mTOR dual inhibitor NVP-BEZ235 stimulates mutant p53 degradation to exert anti-tumor effects on triple-negative breast cancer cells.
- Source :
-
FEBS open bio [FEBS Open Bio] 2020 Apr; Vol. 10 (4), pp. 535-545. Date of Electronic Publication: 2020 Mar 06. - Publication Year :
- 2020
-
Abstract
- 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.<br /> (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)
- Subjects :
- Autophagy drug effects
Autophagy genetics
Cell Line, Tumor
Cell Movement drug effects
Cell Proliferation drug effects
Cell Survival drug effects
Female
Humans
Mutant Proteins genetics
Phosphatidylinositol 3-Kinases metabolism
Proto-Oncogene Proteins c-akt metabolism
Signal Transduction genetics
TOR Serine-Threonine Kinases metabolism
Transfection
Triple Negative Breast Neoplasms pathology
Tumor Suppressor Protein p53 genetics
Antineoplastic Agents pharmacology
Imidazoles pharmacology
Mutant Proteins metabolism
Phosphoinositide-3 Kinase Inhibitors pharmacology
Proteolysis drug effects
Quinolines pharmacology
Signal Transduction drug effects
TOR Serine-Threonine Kinases antagonists & inhibitors
Triple Negative Breast Neoplasms metabolism
Tumor Suppressor Protein p53 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2211-5463
- Volume :
- 10
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- FEBS open bio
- Publication Type :
- Academic Journal
- Accession number :
- 32027103
- Full Text :
- https://doi.org/10.1002/2211-5463.12806