beta-TrCP1 degradation is a novel action mechanism of PI3K/mTOR inhibitors in triple-negative breast cancer cells.
- Author:
Yong Weon YI
1
;
Hyo Jin KANG
;
Edward Jeong BAE
;
Seunghoon OH
;
Yeon Sun SEONG
;
Insoo BAE
Author Information
- Publication Type:Original Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
- MeSH: Cell Line, Tumor; Cell Proliferation; Cell Survival/drug effects; Cyclin E/genetics/metabolism; Dose-Response Relationship, Drug; Female; Furans/pharmacology; Gene Knockdown Techniques; Humans; Models, Biological; Multiprotein Complexes/antagonists & inhibitors; Phosphatidylinositol 3-Kinases/*antagonists & inhibitors; Phosphorylation/drug effects; Protein Kinase Inhibitors/*pharmacology; Proteolysis/drug effects; Proto-Oncogene Proteins c-myc/genetics/metabolism; Pyridines/pharmacology; Pyrimidines/pharmacology; TOR Serine-Threonine Kinases/*antagonists & inhibitors; Triple Negative Breast Neoplasms/genetics/*metabolism; beta-Transducin Repeat-Containing Proteins/genetics/*metabolism
- From:Experimental & Molecular Medicine 2015;47(2):e143-
- CountryRepublic of Korea
- Language:English
- Abstract: An F-box protein, beta-TrCP recognizes substrate proteins and destabilizes them through ubiquitin-dependent proteolysis. It regulates the stability of diverse proteins and functions as either a tumor suppressor or an oncogene. Although the regulation by beta-TrCP has been widely studied, the regulation of beta-TrCP itself is not well understood yet. In this study, we found that the level of beta-TrCP1 is downregulated by various protein kinase inhibitors in triple-negative breast cancer (TNBC) cells. A PI3K/mTOR inhibitor PI-103 reduced the level of beta-TrCP1 in a wide range of TNBC cells in a proteasome-dependent manner. Concomitantly, the levels of c-Myc and cyclin E were also downregulated by PI-103. PI-103 reduced the phosphorylation of beta-TrCP1 prior to its degradation. In addition, knockdown of beta-TrCP1 inhibited the proliferation of TNBC cells. We further identified that pharmacological inhibition of mTORC2 was sufficient to reduce the beta-TrCP1 and c-Myc levels. These results suggest that mTORC2 regulates the stability of beta-TrCP1 in TNBC cells and targeting beta-TrCP1 is a potential approach to treat human TNBC.
