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

Yong Weon Yi; Hyo Jin Kang; Edward Jeong Bae; Seunghoon Oh; Yeon-Sun Seong; Insoo Bae

doi:10.1038/emm.2014.127

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

Exp Mol Med. 2015 Feb 27;47(2):e143. doi: 10.1038/emm.2014.127.

Authors

Yong Weon Yi¹, Hyo Jin Kang², Edward Jeong Bae³, Seunghoon Oh⁴, Yeon-Sun Seong¹, Insoo Bae¹

Affiliations

¹ 1] Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA [2] Department of Nanobiomedical Science & BK21 PLUS Research Center for Regenerative Medicine, Dankook University, Cheonan, Korea.
² Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
³ 1] Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA [2] Department of Nursing and Health Studies, Georgetown University, Washington, DC, USA.
⁴ Department of Physiology, College of Medicine, Dankook University, Cheonan, Korea.

Abstract

An F-box protein, β-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 β-TrCP has been widely studied, the regulation of β-TrCP itself is not well understood yet. In this study, we found that the level of β-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 β-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 β-TrCP1 prior to its degradation. In addition, knockdown of β-TrCP1 inhibited the proliferation of TNBC cells. We further identified that pharmacological inhibition of mTORC2 was sufficient to reduce the β-TrCP1 and c-Myc levels. These results suggest that mTORC2 regulates the stability of β-TrCP1 in TNBC cells and targeting β-TrCP1 is a potential approach to treat human TNBC.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cell Proliferation
Cell Survival / drug effects
Cyclin E / genetics
Cyclin E / metabolism
Dose-Response Relationship, Drug
Female
Furans / pharmacology
Gene Knockdown Techniques
Humans
Mechanistic Target of Rapamycin Complex 2
Models, Biological
Multiprotein Complexes / antagonists & inhibitors
Phosphoinositide-3 Kinase Inhibitors*
Phosphorylation / drug effects
Protein Kinase Inhibitors / pharmacology*
Proteolysis / drug effects
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
Pyridines / pharmacology
Pyrimidines / pharmacology
TOR Serine-Threonine Kinases / antagonists & inhibitors*
Triple Negative Breast Neoplasms / genetics
Triple Negative Breast Neoplasms / metabolism*
beta-Transducin Repeat-Containing Proteins / genetics
beta-Transducin Repeat-Containing Proteins / metabolism*

Substances

Cyclin E
Furans
Multiprotein Complexes
PI103
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-myc
Pyridines
Pyrimidines
beta-Transducin Repeat-Containing Proteins
Mechanistic Target of Rapamycin Complex 2
TOR Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding