Document Detail


Autophagy and reactive oxygen species modulate cytotoxicity induced by suppression of ATM kinase activity in head and neck cancer cells.
MedLine Citation:
PMID:  22763242     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVES: Because Ataxia Telangiectasia Mutated (ATM)-deficient cells are hypersensitive to ionizing irradiation and DNA-damaging agents, ATM kinase inhibition is thought to enhance radiochemotherapy efficacy. In this study, we investigated the roles of autophagy and reactive oxygen species (ROS) in modulating cytotoxicity induced by suppression of ATM kinase in head and neck cancer cells.
MATERIALS AND METHODS: We use KU55933 to inhibit ATM kinase activity. The cell viability was determined by MTT assays. Autophagy was examined by Western blot for LC3-II and microscopy for acidic vesicles and EGFP-LC3 punctate formation. DCF-DA staining and flow cytometry were used for analyzing ROS generation.
RESULTS: we found that KU55933 reduced cell viability in several head and neck cancer cell lines. KU55933-treated cells showed increased cytoplasmic vesicles, LC3-II accumulation, and EGFP-LC3 punctate formation, indicating that autophagy was induced. KU55933 also increased ROS generation, which was required for autophagy induction because the ROS scavenger N-acetyl-L-cysteine could reduce LC3-II accumulation. KU55933-induced autophagy played a cytoprotective role against ROS-mediated cytotoxicity because autophagy inhibition by chloroquine augmented KU55933's cytotoxicity. In addition, KU55933 reduced cisplatin-resistant head and neck cancer cell viabilities, and induced LC3-II accumulation in these cells.
CONCLUSION: Together, these results shed light on KU55933's therapeutic values as well as autophagy inhibitors in treating primary and cisplatin-resistant head and neck cancers.
Authors:
Chang-Shen Lin; Yu-Chu Wang; Jau-Ling Huang; Chi-Chun Hung; Jeff Yi-Fu Chen
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-07-03
Journal Detail:
Title:  Oral oncology     Volume:  48     ISSN:  1879-0593     ISO Abbreviation:  Oral Oncol.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-23     Completed Date:  2013-05-29     Revised Date:  2014-07-31    
Medline Journal Info:
Nlm Unique ID:  9709118     Medline TA:  Oral Oncol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1152-8     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Ltd. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Ataxia Telangiectasia Mutated Proteins
Autophagy / drug effects*
Blotting, Western
Cell Cycle Proteins / antagonists & inhibitors
Cytoplasmic Vesicles / drug effects,  metabolism
DNA-Binding Proteins / antagonists & inhibitors
Drug Resistance, Neoplasm / drug effects*
Flow Cytometry
Green Fluorescent Proteins / drug effects,  metabolism
Head and Neck Neoplasms / metabolism*
Humans
Microscopy
Microtubule-Associated Proteins / drug effects,  metabolism
Morpholines / pharmacology*
Protein-Serine-Threonine Kinases / antagonists & inhibitors
Pyrones / pharmacology*
Reactive Oxygen Species / metabolism*
Tumor Suppressor Proteins / antagonists & inhibitors
Chemical
Reg. No./Substance:
0/2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; 0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/Microtubule-Associated Proteins; 0/Morpholines; 0/Pyrones; 0/Reactive Oxygen Species; 0/Tumor Suppressor Proteins; 0/enhanced green fluorescent protein; 0/light chain 3, human; 147336-22-9/Green Fluorescent Proteins; EC 2.7.11.1/ATM protein, human; EC 2.7.11.1/Ataxia Telangiectasia Mutated Proteins; EC 2.7.11.1/Protein-Serine-Threonine Kinases

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