NBM-T-BBX-OS01, Semisynthesized from Osthole, Induced G1 Growth Arrest through HDAC6 Inhibition in Lung Cancer Cells
Journal
Molecules
Journal Volume
20
Journal Issue
5
Pages
8000-8019
Date Issued
2015
Author(s)
Pai, Jih-Tung
Hsu, Chia-Yun
Hua, Kuo-Tai
Yu, Sheng-Yung
Huang, Chung-Yang
Chen, Chia-Nan
Liao, Chiung-Ho
Abstract
Disrupting lung tumor growth via histone deacetylases (HDACs) inhibition is a strategy for cancer therapy or prevention. Targeting HDAC6 may disturb the maturation of heat shock protein 90 (Hsp90) mediated cell cycle regulation. In this study, we demonstrated the effects of semisynthesized NBM-T-BBX-OS01 (TBBX) from osthole on HDAC6-mediated growth arrest in lung cancer cells. The results exhibited that the anti-proliferative activity of TBBX in numerous lung cancer cells was more potent than suberoylanilide hydroxamic acid (SAHA), a clinically approved pan-HDAC inhibitor, and the growth inhibitory effect has been mediated through G1 growth arrest. Furthermore, the protein levels of cyclin D1, CDK2 and CDK4 were reduced while cyclin E and CDK inhibitor, p21Waf1/Cip1, were up-regulated in TBBX-treated H1299 cells. The results also displayed that TBBX inhibited HDAC6 activity via down-regulation HDAC6 protein expression. TBBX induced Hsp90 hyper-acetylation and led to the disruption of cyclin D1/Hsp90 and CDK4/Hsp90 association following the degradation of cyclin D1 and CDK4 proteins through proteasome. Ectopic expression of HDAC6 rescued TBBX-induced G1 arrest in H1299 cells. Conclusively, the data suggested that TBBX induced G1 growth arrest may mediate HDAC6-caused Hsp90 hyper-acetylation and consequently increased the degradation of cyclin D1 and CDK4. ? 2015 by the authors; licensee MDPI.
SDGs
Other Subjects
CDK2 protein, human; CDK4 protein, human; coumarin derivative; cyclin dependent kinase 2; cyclin dependent kinase 4; cyclin dependent kinase inhibitor 1A; HDAC6 protein, human; heat shock protein 90; histone deacetylase; histone deacetylase inhibitor; hydroxamic acid; osthole; proteasome; acetylation; cell cycle checkpoint; cell cycle G1 phase; cell proliferation; chemistry; down regulation; drug effects; human; lung tumor; metabolism; tumor cell line; upregulation; Acetylation; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Coumarins; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p21; Down-Regulation; G1 Phase; Histone Deacetylase Inhibitors; Histone Deacetylases; HSP90 Heat-Shock Proteins; Humans; Hydroxamic Acids; Lung Neoplasms; Proteasome Endopeptidase Complex; Up-Regulation
Type
journal article