Involvement of mtDNA Damage Elicited by Oxidative Stress in the Arsenical Skin Cancers

Abstract

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.

Comparison of oxidative stress on DNA, protein and lipids in patients with actinic keratosis, Bowen's disease and squamous cell carcinoma

“…6,15 In skin, 8-OHdG expression is induced by UVR in normal human epidermis 16 and increased in arsenic-induced BD. 17 We document that 8-OHdG is overexpressed in AK and BD tissue compared with adjacent non-lesional tissue, healthy controls and SCC.…”

Nicotinamide Enhances Repair of Arsenic and Ultraviolet Radiation-Induced DNA Damage in HaCaT Keratinocytes and Ex Vivo Human Skin

“…Arsenite was previously reported to diminish cellular antioxidant responses [ 31 ], which would also result in formation of more 8oxoG. Recent studies have however suggested that arsenite exposure at concentrations similar to ours may cause some increase in gene expression levels of DNA repair enzymes such as the 8oxoG repair enzyme human 8-oxoguanine DNA N-glycosylase 1 (hOGG1) [ 10 ]. Arsenic-induced ROS are also thought to contribute to PARP-1 inhibition and subsequent impairment of DNA repair [ 32 ].…”

“…No skin cancers developed in unirradiated, arsenic-exposed mice [ 9 ]. Furthermore, in humans, arsenic-induced Bowen’s disease contained higher levels of 8oxoG compared to non arsenic-induced Bowen’s disease [ 10 ].…”

The interaction of arsenic and N-butyl-N-(4-hydroxybutyl)nitrosamine on urothelial carcinogenesis in mice

“…For example, some studies have proven that arsenic induces oxidative stress and DNA damage. Arsenic increases DNA 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in mouse urothelium [ 12 , 30 ] as well as enhances oxidative stress and 8-OHdG levels in the mitochondria DNA of keratinocytes [ 31 ]. BBN also increases DNA 8-OHdG levels and arsenic has an additional effect on mouse urothelium [ 12 ].…”