REV1 is implicated in the development of carcinogen-induced lung cancer.
The somatic mutation hypothesis of cancer predicts that reducing the frequency of mutations induced by carcinogens will reduce the incidence of cancer. To examine this, we developed an antimutator strategy based on the manipulation of the level of a protein required for mutagenic bypass of DNA damage induced by the ubiquitous carcinogen benzo[a]pyrene. The expression of this protein, REV1, was reduced in mouse cells using a vector encoding a gene-specific targeting ribozyme. In the latter cells, mutagenesis induced by the activated form of benzo[a]pyrene was reduced by >90%. To examine if REV1 transcripts could be lowered in vivo, the plasmid was complexed with polyethyleneimine, a nonviral cationic polymer, and delivered to the lung via aerosol. The endogenous REV1 transcript in the bronchial epithelium as determined by quantitative real-time PCR in laser capture microdissected cells was reduced by 60%. There was a significant decrease in the multiplicity of carcinogen-induced lung tumors from 6.4 to 3.7 tumors per mouse. Additionally, REV1 inhibition completely abolished tumor formation in 27% of the carcinogen-exposed mice. These data support the central role of the translesion synthesis pathway in the development of lung cancer. Further, the selective modulation of members of this pathway presents novel potential targets for cancer prevention. The somatic mutation hypothesis of cancer predicts that the frequency of cancers will also be reduced.
Dumstorf
Chad A
CA
Department of Pharmacology, University of Louisville, Louisville, KY 40202, USA.
Mukhopadhyay
Suparna
S
Krishnan
Elangovan
E
Haribabu
Bodduluri
B
McGregor
W Glenn
WG
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000633:toxicity*; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004259:DNA-Directed DNA Polymerase; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016296:Mutagenesis; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors / Q000502:physiology*; D016337:RNA, Catalytic / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000099270:Y-Family DNA Polymerases
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D002273:Carcinogens; D004259:DNA-Directed DNA Polymerase; D009713:Nucleotidyltransferases; D016337:RNA, Catalytic; D012333:RNA, Messenger; C496086:Rev1 protein, mouse; D000099270:Y-Family DNA Polymerases