Exp Mol Med.  2015 Feb;47(2):e143. 10.1038/emm.2014.127.

beta-TrCP1 degradation is a novel action mechanism of PI3K/mTOR inhibitors in triple-negative breast cancer cells

• Yi YW
• Kang HJ
• Bae EJ
• Oh S
• Seong YS
• Bae I

• KMID: 2155408
• DOI: http://doi.org/10.1038/emm.2014.127

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.

MeSH Terms

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
Cyclin E
Furans
Multiprotein Complexes
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-myc
Pyridines
Pyrimidines
Phosphatidylinositol 3-Kinases
TOR Serine-Threonine Kinases
beta-Transducin Repeat-Containing Proteins