title: Aberrant cell proliferation by enhanced mitochondrial biogenesis via mtTFA in arsenical skin cancers.
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.
authors.affiliation: Department of Dermatology, Graduate Institute of Medicine, Center of Excellence for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Lee
authors.forename: Shi-Bei
authors.initials: SB
authors.lastname: Wu
authors.forename: Chien-Hui
authors.initials: CH
authors.lastname: Hong
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Liao
authors.forename: Ching-Ying
authors.initials: CY
authors.lastname: Wu
authors.forename: Gwo-Shing
authors.initials: GS
authors.lastname: Chen
authors.forename: Yau-Huei
authors.initials: YH
authors.lastname: Wei
authors.forename: Hsin-Su
authors.initials: HS
authors.lastname: Yu
mesh_terms: D000368:Aged; D001151:Arsenic / Q000009:adverse effects; D020261:Arsenic Poisoning / Q000150:complications*; D015153:Blotting, Western; D001913:Bowen's Disease / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects*; D019069:Cell Respiration / Q000187:drug effects / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D014157:Transcription Factors; C422562:mitochondrial transcription factor A; D001151:Arsenic