Obtusilactone A and (-)-sesamin induce apoptosis in human lung cancer cells by inhibiting mitochondrial Lon protease and activating DNA damage checkpoints
Journal
Cancer Science
Journal Volume
101
Journal Issue
12
Pages
2612-2620
Date Issued
2010
Author(s)
Wang, H.-H.
Cheng, K.-C.
Lin, C.-J.
Hsu, S.-W.
Fang, W.-C.
Hsu, T.-F.
Chiu, C.-C.
Chang, H.-H.
Lee, A.Y.-L.
Abstract
Several compounds from Cinnamomum kotoense show anticancer activities. However, the detailed mechanisms of most compounds from C. kotoense remain unknown. In this study, we investigated the anticancer activity of obtusilactone A (OA) and (-)-sesamin in lung cancer. Our results show that human Lon is upregulated in non-small-cell lung cancer (NSCLC) cell lines, and downregulation of Lon triggers caspase-3 mediated apoptosis. Through enzyme-based screening, we identified two small-molecule compounds, obtusilactone A (OA) and (-)-sesamin from C. kotoense, as potent Lon protease inhibitors. Obtusilactone A and (-)-sesamin interact with Ser855 and Lys898 residues in the active site of the Lon protease according to molecular docking analysis. Thus, we suggest that cancer cytotoxicity of the compounds is partly due to the inhibitory effects on Lon protease. In addition, the compounds are able to cause DNA double-strand breaks and activate checkpoints. Treatment with OA and (-)-sesamin induced p53-independent DNA damage responses in NSCLC cells, including G1/S checkpoint activation and apoptosis, as evidenced by phosphorylation of checkpoint proteins (H2AX, Nbs1, and Chk2), caspase-3 cleavage, and sub-G1 accumulation. In conclusion, OA and (-)-sesamin act as both inhibitors of human mitochondrial Lon protease and DNA damage agents to activate the DNA damage checkpoints as well induce apoptosis in NSCLC cells. These dual functions open a bright avenue to develop more selective chemotherapy agents to overcome chemoresistance and sensitize cancer cells to other chemotherapeutics. (Cancer Sci 2010; 101: 2612-2620) ? 2010 Japanese Cancer Association.
SDGs
Other Subjects
antineoplastic agent; caspase 3; checkpoint kinase 2; double stranded DNA; endopeptidase La; histone H2AX; lysine; nibrin; obtusilactone a; protein p53; serine; serine proteinase inhibitor; sesamin; unclassified drug; antineoplastic activity; apoptosis; article; cancer cell culture; cell cycle arrest; cell cycle G1 phase; cell cycle regulation; cell cycle S phase; Cinnamomum; Cinnamomum kotoense; concentration response; controlled study; DNA damage; double stranded DNA break; down regulation; drug cytotoxicity; drug mechanism; drug potency; enzyme active site; enzyme assay; human; human cell; human cell culture; lung cancer; lung non small cell cancer; molecular docking; nucleotide sequence; priority journal; protein phosphorylation; proteinase inhibition; signal transduction; upregulation; Amino Acid Sequence; Antineoplastic Agents; Apoptosis; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Separation; Comet Assay; Dioxoles; DNA Damage; Flow Cytometry; Humans; Lignans; Lung Neoplasms; Mitochondria; Molecular Sequence Data; Protease La; Protein Structure, Quaternary; Signal Transduction
Type
journal article