Document Detail


Aberrant cell proliferation by enhanced mitochondrial biogenesis via mtTFA in arsenical skin cancers.
MedLine Citation:
PMID:  21514422     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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.
Affiliation:
Department of Dermatology, Graduate Institute of Medicine, Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
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MeSH Terms
Descriptor/Qualifier:
Aged
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*
Humans
Immunohistochemistry
Keratinocytes / drug effects,  metabolism
Mitochondria / drug effects*
Mitochondrial Proteins / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Skin Neoplasms / chemically induced,  metabolism,  pathology*
Transcription Factors / metabolism*
Chemical
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Mitochondrial Proteins; 0/Transcription Factors; 0/mitochondrial transcription factor A; 7440-38-2/Arsenic
Comments/Corrections
Comment In:
Am J Pathol. 2011 May;178(5):1949-52   [PMID:  21514412 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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