Involvement of mtDNA damage elicited by oxidative stress in the arsenical skin cancers.
Arsenic causes several human cancers. Arsenic-induced Bowen's disease (As-BD), the most common arsenical cancer, is characterized by increased proliferation, dysplasia, and individual cell apoptosis, all of which involve mitochondria. We reported that arsenic causes aberrant keratinocyte proliferation through mtTFA-mediated mitochondrial biogenesis in As-BD. Increasing mitochondrial biogenesis causes cells to undergo oxidative stress. However, how arsenic induces oxidative stress and causes mtDNA damage in arsenical cancers remains largely unknown. Using tissues from As-BD patients and arsenic-treated keratinocytes, we determined the oxidative stress, antioxidant enzymes, DNA-repair enzymes, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) level in mtDNA by immunofluorescence, real-time PCR, and western blot. The results showed that oxidative stress was enhanced in both As-BD and arsenic-treated keratinocytes. Antioxidant enzymes including manganese-superoxide anion and copper/zinc-superoxide anion and DNA-repair enzymes were upregulated concomitantly in tissues and cells. In arsenic-treated keratinocytes, increased mitochondrial oxidative stress and the 8-OHdG level in mtDNA were attenuated by pretreatment with ascorbic acid, a potent antioxidant. Further, we found several somatic mutations in the ND4, ND5, and ND6 genes of mtDNA in lesional but not in perilesional skin from As-BD patients. Taken together, the results suggest that oxidative damage and mutations to mtDNA might be involved in the arsenical skin cancers in the context of mitochondrial biogenesis.
Department of Dermatology, Kaohsiung Municipal Hsiao-Kang Hospital and Kaohsiung Medical University, Kaohsiung, Taiwan.
Chih-Hung
CH
Lee
Shi-Bei
SB
Wu
Chien-Hui
CH
Hong
Gwo-Shin
GS
Chen
Yau-Huei
YH
Wei
Hsin-Su
HS
Yu
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000368:Aged; D000369:Aged, 80 and over; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001151:Arsenic / Q000009:adverse effects* / Q000494:pharmacology; D001913:Bowen's Disease / Q000139:chemically induced* / Q000235:genetics / Q000503:physiopathology*; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology*; D045643:DNA Repair Enzymes / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics / Q000502:physiology*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D018384:Oxidative Stress / Q000502:physiology*; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000503:physiopathology*; D013481:Superoxides / Q000378:metabolism
D000975:Antioxidants; D004272:DNA, Mitochondrial; D013481:Superoxides; D000080242:8-Hydroxy-2'-Deoxyguanosine; D045643:DNA Repair Enzymes; D003849:Deoxyguanosine; D001151:Arsenic