Inhibition of 7,12-dimethylbenz(a)anthracene-induced skin tumorigenesis in C57BL/6 mice by sulforaphane is mediated by nuclear factor E2-related factor 2.
Sulforaphane, a dietary isothiocyanate, possesses potent chemopreventive effects through the induction of cellular detoxifying/antioxidant enzymes via the transcription factor nuclear factor E2-related factor 2 (Nrf2). To investigate carcinogenesis mechanisms related to the regulation of Nrf2, we examined the tumor incidence and tumor numbers per mouse in Nrf2 wild-type (+/+) and Nrf2 knockout (-/-) mice. 7,12-Dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate treatments resulted in an increase in the incidence of skin tumors and tumor numbers per mouse in both genotypes; however, both indices were markedly higher in Nrf2(-/-) mice as compared with Nrf2(+/+) mice. Western blot analysis revealed that Nrf2 as well as heme oxygenase-1, a protein regulated by Nrf2 were not expressed in skin tumors from mice of either genotype, whereas expression of heme oxygenase-1 in Nrf2(+/+) mice was much higher than that in Nrf2(-/-) mice in nontumor skin samples. Next, we examined the chemopreventive efficacy of sulforaphane in mice with both genotypes. Topical application of 100 nmol of sulforaphane once a day for 14 days prior to 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate applications decreased the incidence of skin tumor in the Nrf2(+/+) mice when compared with the vehicle-treated group. Importantly, there was no chemoprotective effect elicited by sulforaphane pretreatment in the Nrf2(-/-) mice group. Taken together, our results show for the first time that Nrf2(-/-) mice are more susceptible to skin tumorigenesis and that the chemopreventive effects of sulforaphane are mediated, at least in part, through Nrf2.
Xu
Changjiang
C
Center for Cancer Prevention Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Huang
Mou-Tuan
MT
Shen
Guoxiang
G
Yuan
Xiaoling
X
Lin
Wen
W
Khor
Tin Oo
TO
Conney
Allan H
AH
Kong
Ah-Ng Tony
AN
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D004198:Disease Susceptibility; D017879:Isothiocyanates; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050983:NF-E2 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016133:Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D013454:Sulfoxides; D013861:Thiocyanates / Q000627:therapeutic use*
D016588:Anticarcinogenic Agents; D004273:DNA, Neoplasm; D017879:Isothiocyanates; D050983:NF-E2 Transcription Factor; D013454:Sulfoxides; D013861:Thiocyanates; D015127:9,10-Dimethyl-1,2-benzanthracene; C016766:sulforaphane