title: 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.affiliation: 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.
authors.forename: Yong Weon
authors.initials: YW
authors.lastname: Yi
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Kang
authors.affiliation: 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.
authors.forename: Edward Jeong
authors.initials: EJ
authors.lastname: Bae
authors.affiliation: Department of Physiology, College of Medicine, Dankook University, Cheonan, Korea.
authors.forename: Seunghoon
authors.initials: S
authors.lastname: Oh
authors.affiliation: 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.
authors.forename: Yeon-Sun
authors.initials: YS
authors.lastname: Seong
authors.affiliation: 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.
authors.forename: Insoo
authors.initials: I
authors.lastname: Bae
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005663:Furans / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D059748:Proteolysis / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019927:Cyclin E; D005663:Furans; D046912:Multiprotein Complexes; C522973:PI103; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D011743:Pyrimidines; D044844:beta-Transducin Repeat-Containing Proteins; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases