Document Detail

Aberrant cell proliferation by enhanced mitochondrial biogenesis via mtTFA in arsenical skin cancers.
MedLine Citation:
PMID:  21514422     Owner:  NLM     Status:  MEDLINE    
Arsenic-induced Bowen's disease (As-BD), a cutaneous carcinoma in situ, is thought to arise from gene mutation and uncontrolled proliferation. However, how mitochondria regulate the arsenic-induced cell proliferation remains unclear. The aim of this study was to clarify whether arsenic interfered with mitochondrial biogenesis and function, leading to aberrant cell proliferation in As-BD. Skin biopsy samples from patients with As-BD and controls were stained for cytochrome c oxidase (Complex IV), measured for mitochondrial DNA (mtDNA) copy number and the expression levels of mitochondrial biogenesis-related genes, including peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (mtTFA). The results showed that expression of cytochrome c oxidase, mtTFA, NRF-1, and PGC-1α was increased in As-BD compared with in healthy subjects. Treatment of primary keratinocytes with arsenic at concentrations lower than 1.0 μmol/L induced cell proliferation, along with enhanced mitochondrial biogenesis. Furthermore, we observed that the mitochondrial oxygen consumption rate and intracellular ATP level were increased in arsenic-treated keratinocytes. Blocking of mitochondrial function by oligomycin A (Complex V inhibitor) or knockdown of mtTFA by RNA interference abrogated arsenic-induced cell proliferation without affecting cyclin D1 expression. We concluded that mtTFA up-regulation, augmented mitochondrial biogenesis, and enhanced mitochondrial functions may contribute to arsenic-induced cell proliferation. Targeting mitochondrial biogenesis may help treat arsenical cancers at the stage of cell proliferation.
Chih-Hung Lee; Shi-Bei Wu; Chien-Hui Hong; Wei-Ting Liao; Ching-Ying Wu; Gwo-Shing Chen; Yau-Huei Wei; Hsin-Su Yu
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The American journal of pathology     Volume:  178     ISSN:  1525-2191     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-04-25     Completed Date:  2011-08-26     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2066-76     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Department of Dermatology, Graduate Institute of Medicine, Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
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MeSH Terms
Arsenic / adverse effects
Arsenic Poisoning / complications*
Blotting, Western
Bowen's Disease / chemically induced,  metabolism,  pathology*
Cell Proliferation / drug effects*
Cell Respiration / drug effects,  physiology
Cell Transformation, Neoplastic / drug effects,  metabolism,  pathology*
DNA-Binding Proteins / metabolism*
Keratinocytes / drug effects,  metabolism
Mitochondria / drug effects*
Mitochondrial Proteins / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Skin Neoplasms / chemically induced,  metabolism,  pathology*
Transcription Factors / metabolism*
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Mitochondrial Proteins; 0/Transcription Factors; 0/mitochondrial transcription factor A; 7440-38-2/Arsenic
Comment In:
Am J Pathol. 2011 May;178(5):1949-52   [PMID:  21514412 ]

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