Abstract
Tobacco smoke (TS) is a major cause of human bladder cancer (BC). Two components in TS, 4-aminobiphenyl (4-ABP) and acrolein, which also are environmental contaminants, can cause bladder tumor in rat models. Their role in TS related BC has not been forthcoming. To establish the relationship between acrolein and 4-ABP exposure and BC, we analyzed acrolein-deoxyguanosine (dG) and 4-ABP-DNA adducts in normal human urothelial mucosa (NHUM) and bladder tumor tissues (BTT), and measured their mutagenicity in human urothelial cells. We found that the acrolein-dG levels in NHUM and BTT are 10-30 fold higher than 4-ABP-DNA adduct levels and that the acrolein-dG levels in BTT are 2 fold higher than in NHUM. Both acrolein-dG and 4-ABP-DNA adducts are mutagenic; however, the former are 5 fold more mutagenic than the latter. These two types of DNA adducts induce different mutational signatures and spectra. We found that acrolein inhibits nucleotide excision and base excision repair and induces repair protein degradation in urothelial cells. Since acrolein is abundant in TS, inhaled acrolein is excreted into urine and accumulates in the bladder and because acrolein inhibits DNA repair and acrolein-dG DNA adducts are mutagenic, we propose that acrolein is a major bladder carcinogen in TS.
Highlights
Bladder cancer is the fifth most frequently found tumor in the United States, with >70,000 incident cases and resulting in >15,000 deaths annually [1, 2]
Acrolein-dG levels in the genomic DNA of normal human urothelial mucosa and bladder tumor tissues were detected by two methods: a 32P-postlabeling method using a two dimensional-thin layer chromatography (TLC)/HPLC and an immunochemical method using a monoclonal antibody against acrolein-dG DNA adducts as the first antibody and a quantum dot-labeled secondary antibody [14]
The results shows that γ-OH-acrolein-dG is the major isomer and α-OH-acrolein-dG is the minor isomer in both normal human urothelial mucosa and bladder tumor tissue, which is similar to the acrolein-dG DNA adducts detected in acrolein-treated cultured human cells [25, 38, 39] (Figures 1A & 1C)
Summary
Bladder cancer is the fifth most frequently found tumor in the United States, with >70,000 incident cases and resulting in >15,000 deaths annually [1, 2]. It is well known that the incidence of bladder cancer in individuals working in the printing, dyeing, and tanning industries is higher than age- and sex- matched controls [5, 7]. Ample evidence from both epidemiological studies and animal models has firmly established that arylamines, 4-aminobiphenyl (4-ABP), are the major culprits in bladder cancer related to occupational exposures [8, 9]. These results www.impactjournals.com/oncotarget establish a molecular link between carcinogen-induced DNA damage and the p53 mutational patterns in bladder cancer
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