beta-TrCP1 degradation is a novel action mechanism of PI3K/mTOR inhibitors in triple-negative breast cancer cells
Experimental & Molecular Medicine
; : e143-2015.
Article
in English
| WPRIM (Western Pacific)
| ID: wpr-42472
Responsible library:
WPRO
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.
Full text:
Available
Database:
WPRIM (Western Pacific)
Main subject:
Phosphorylation
/
Pyridines
/
Pyrimidines
/
Cell Survival
/
Proto-Oncogene Proteins c-myc
/
Phosphatidylinositol 3-Kinases
/
Cyclin E
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Cell Line, Tumor
/
Beta-Transducin Repeat-Containing Proteins
/
Multiprotein Complexes
Limits:
Female
/
Humans
Language:
English
Journal:
Experimental & Molecular Medicine
Year:
2015
Document type:
Article