ERK activation in arsenite-treated G1-enriched CL3 cells contributes to survival, DNA repair inhibition, and micronucleus formation.
Arsenite is known to induce chromosomal damage and extracellular signal-regulated kinases 1/2 (ERK) signaling transduction pathway. Arsenite also perturbs mitotic spindle and induces G2/M prolongation, leading to genomic instability. However, little is known concerning whether G1 phase is susceptible to arsenite in causing genomic instability and ERK activation. In this study, we investigate the roles of ERK activation in survival, micronucleus formation, and nucleotide excision repair (NER) synthesis in arsenite-treated G1-enriched CL3 human non-small-cell lung carcinoma cells. We found that G1 was the most insensitive phase to arsenite cytotoxicity, yet it was highly susceptible to arsenite in micronucleus induction. After arsenite exposure, the G1 cells exhibited a marked retard in the formation of binucleated cells when they were cultured in cytochalasin B, an inhibitor of cytokinesis, suggesting that arsenite delays the cell cycle progression. Arsenite activated sustained-ERK signal in G1 cells whose suppression further decreased cell proliferation and survival and could lower the micronucleus induction. The NER synthesis activity of G1 cells was inhibited by arsenite as a function of the extent of ERK activation. Intriguingly, blockage of ERK activation recovered NER synthesis activity in the arsenite-treated G1 cells. Together, these results suggest that ERK activation in arsenite-treated G1 cells counteracts cytotoxicity and contributes to genomic instability via NER synthesis inhibition and micronucleus induction.
Li
Ju-Pi
JP
Molecular Carcinogenesis Laboratory, Institute of Biotechnology and Department of Life Sciences, National Tsing Hua University, Hsinchu 300, Taiwan.
Lin
Jin-Ching
JC
Yang
Jia-Ling
JL
D018053:Arsenites / Q000633:toxicity*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced*
D018053:Arsenites; D004273:DNA, Neoplasm; C015001:arsenite