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Aberrant cell proliferation by enhanced mitochondrial biogenesis via mtTFA in arsenical skin cancers
- Source :
- The American journal of pathology. 178(5)
- Publication Year :
- 2009
-
Abstract
- 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.
- Subjects :
- Keratinocytes
Mitochondrial DNA
Skin Neoplasms
Blotting, Western
Cell Respiration
Bowen's Disease
Mitochondrion
Biology
Gene mutation
Pathology and Forensic Medicine
Arsenic
Mitochondrial Proteins
Arsenic Poisoning
Cytochrome c oxidase
Animals
Humans
NRF1
Aged
Cell Proliferation
integumentary system
Cell growth
Reverse Transcriptase Polymerase Chain Reaction
Regular Article
TFAM
Immunohistochemistry
Cell biology
Mitochondria
DNA-Binding Proteins
Cell Transformation, Neoplastic
Mitochondrial biogenesis
Immunology
biology.protein
Commentary
Transcription Factors
Subjects
Details
- ISSN :
- 15252191
- Volume :
- 178
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- The American journal of pathology
- Accession number :
- edsair.doi.dedup.....a9b7e04ff414fd67da55a57d7fa51e41