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Lithocholic Acid Hydroxyamide Destabilizes Cyclin D1 and Induces G 0 /G 1 Arrest by Inhibiting Deubiquitinase USP2a.
- Source :
-
Cell chemical biology [Cell Chem Biol] 2017 Apr 20; Vol. 24 (4), pp. 458-470.e18. Date of Electronic Publication: 2017 Mar 23. - Publication Year :
- 2017
-
Abstract
- USP2a is a deubiquitinase responsible for stabilization of cyclin D1, a crucial regulator of cell-cycle progression and a proto-oncoprotein overexpressed in numerous cancer types. Here we report that lithocholic acid (LCA) derivatives are inhibitors of USP proteins, including USP2a. The most potent LCA derivative, LCA hydroxyamide (LCAHA), inhibits USP2a, leading to a significant Akt/GSK3β-independent destabilization of cyclin D1, but does not change the expression of p27. This leads to the defects in cell-cycle progression. As a result, LCAHA inhibits the growth of cyclin D1-expressing, but not cyclin D1-negative cells, independently of the p53 status. We show that LCA derivatives may be considered as future therapeutics for the treatment of cyclin D1-addicted p53-expressing and p53-defective cancer types.<br /> (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Subjects :
- Catalytic Domain
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Cyclin D1 antagonists & inhibitors
Cyclin D1 genetics
Cyclin-Dependent Kinase Inhibitor p21 metabolism
Cyclin-Dependent Kinase Inhibitor p27 metabolism
Cycloheximide chemistry
Cycloheximide pharmacology
Down-Regulation drug effects
Endopeptidases chemistry
Endopeptidases genetics
Glycogen Synthase Kinase 3 beta metabolism
HCT116 Cells
Humans
Lithocholic Acid pharmacology
MCF-7 Cells
Proto-Oncogene Proteins c-akt metabolism
RNA Interference
Signal Transduction drug effects
Tumor Suppressor Protein p53 deficiency
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Protein p53 metabolism
Ubiquitin Thiolesterase
Cyclin D1 metabolism
Endopeptidases metabolism
G1 Phase Cell Cycle Checkpoints drug effects
Lithocholic Acid analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 2451-9448
- Volume :
- 24
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cell chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 28343940
- Full Text :
- https://doi.org/10.1016/j.chembiol.2017.03.002