Acrolein is a major cigarette-related lung cancer agent: Preferential binding at p53 mutational hotspots and inhibition of DNA repair.
The tumor suppressor gene p53 is frequently mutated in cigarette smoke (CS)-related lung cancer. The p53 binding pattern of carcinogenic polycyclic aromatic hydrocarbons (PAHs) found in CS coincides with the p53 mutational pattern found in lung cancer, and PAHs have thus been considered to be major culprits for lung cancer. However, compared with other carcinogenic compounds, such as aldehydes, the amount of PAHs in CS is minute. Acrolein (Acr) is abundant in CS, and it can directly adduct DNA. Acr-DNA adducts, similar to PAH-DNA adducts, induce predominantly G-to-T transversions in human cells. These findings raise the question of whether Acr-DNA adducts are responsible for p53 mutations in CS-related lung cancer. To determine the role of Acr-DNA adducts in p53 mutagenesis in CS-related lung cancer we mapped the distribution of Acr-DNA adducts at the sequence level in the p53 gene of lung cells using the UvrABC incision method in combination with ligation-mediated PCR. We found that the Acr-DNA binding pattern is similar to the p53 mutational pattern in human lung cancer. Acr preferentially binds at CpG sites, and this enhancement of binding is due to cytosine methylation at these sequences. Furthermore, we found that Acr can greatly reduce the DNA repair capacity for damage induced by benzo[a]pyrene diol epoxide. Together these results suggest that Acr is a major etiological agent for CS-related lung cancer and that it contributes to lung carcinogenesis through two detrimental effects: DNA damage and inhibition of DNA repair.
Feng
Zhaohui
Z
Department of Environmental Medicine, Pathology, and Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
Hu
Wenwei
W
Hu
Yu
Y
Tang
Moon-shong
MS
D000171:Acrolein / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D001665:Binding Sites; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D002460:Cell Line; D018899:CpG Islands; D018736:DNA Adducts; D004249:DNA Damage; D019175:DNA Methylation; D004260:DNA Repair; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology*; D015394:Molecular Structure; D009154:Mutation; D012907:Smoking / Q000009:adverse effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D002273:Carcinogens; D018736:DNA Adducts; D016159:Tumor Suppressor Protein p53; D000171:Acrolein