As(III) inhibits ultraviolet radiation-induced cyclobutane pyrimidine dimer repair via generation of nitric oxide in human keratinocytes

Abstract

Inorganic arsenic enhances skin tumor formation when combined with other carcinogens including ultraviolet radiation (UVR). The inhibition of DNA damage repair by arsenic has been hypothesized to contribute to the co-carcinogenic activities of arsenic observed in vivo. Cyclobutane pyrimidine dimers (CPDs) are an important mutagenic UVR photoproduct and implicated in the genesis of nonmelanoma skin cancer. The current study demonstrates that low concentrations of arsenite (As(III)) inhibit UVR-induced CPDs repair in a human keratinocyte cell line via nitric oxide (NO) and inducible nitric oxide synthase (iNOS). Following As(III) treatment, NO production and iNOS expression are elevated. Little is known about regulation of iNOS by As(III) and further investigations indicated that p38 mitogen-activated protein kinase (p38 MAPK) and NF-κB are required for As(III) induction of iNOS expression. This As(III)-stimulated signaling cascade was involved in inhibition of UVR-induced CPDs repair as disruption of p38 MAPK activity and NF-κB nuclear translocation counteracted the effects of As(III) on CPD repair. Selective inhibition of iNOS ameliorated As(III) inhibition of CPDs repair thereby suggesting that iNOS is a downstream mediator of As(III) activity. These findings provide evidence that an As(III) stimulated signal transduction cascade culminating in elevated iNOS expression and NO generation is an underlying mechanism for inhibition of UVR-induced DNA damage repair by arsenic.

Inhibition of nucleotide excision repair by arsenic

“…They further demonstrated that like nitric oxide generators, arsenite inhibited the DNAadduct excision in NER induced by UVC, 4-nitroquinoline 1-oxide, BPDE, cisplatin, or mitomycin C, but not that in BER induced by methyl methane sulfonate, H 2 O 2 , sodium nitrosoprusside, or 3-morpholinosydnonimine [79]. Their finding was confirmed in human keratinocytes by Ding et al [24] who used different methods for both NO and pyrimidine dimer determinations. It is relevant to point out that although reactive nitrogen oxide species (RNOS) derived from NO can result in strand breaks and mutations, NO itself is probably insufficiently reactive to attack DNA directly [80], which makes this proposal a plausible mechanism for NER inhibition by arsenic, possibly through NO-induced nitrosylation of DNA repair proteins ( Figure 3).…”

“…Furthermore, arsenic reduced unscheduled DNA synthesis (UDS) and the excision of CPDs irradiation. The reported studies of NER inhibition by arsenic [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] are summarized in Supporting Information Table S1.…”

Abnormal Expression of 8-Nitroguanine in the Brain of Mice Exposed to Arsenic Subchronically

“…Moreover, the overproduction of NO is believed to be associated with activation of iNOS, an isoform of NOS 22) . Ding et al also reported that blocking iNOS activity with specific inhibitors abolished increased NO production 23) . Waalkes et al observed that sodium arsenate upregulated iNOS and induced 3-nitrotyrosine in Swiss mice 24) .…”

Arsenic's Interactions with Macromolecules and its Relationship to Carcinogenesis

“…Arsenite inhibited the repair of ultraviolet radiation induced cyclobutane pyrimidine dimers in human keratinocytes [50]. p38 MAPK and NF-kB may mediate this nitric oxide and inducible nitric oxide synthase dependent effect [50]. 5.…”