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

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.

• Authors: Yong Weon Yi, Hyo Jin Kang, Edward Jeong Bae, Seunghoon Oh, Yeon-Sun Seong, Insoo Bae
• Journal: Experimental & molecular medicine (Exp Mol Med) Vol. 47 Pg. e143 (Feb 27 2015) ISSN: 2092-6413 [Electronic] United States
• PMID: 25721419 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Cell Line, Tumor
• Cell Proliferation
• Cell Survival (drug effects)
• Cyclin E (genetics, 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, metabolism)
• Pyridines (pharmacology)
• Pyrimidines (pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Triple Negative Breast Neoplasms (genetics, metabolism)
• beta-Transducin Repeat-Containing Proteins (genetics, metabolism)