Inhibition of Activator Protein
Inhibition of activator protein-1 by sulforaphane involves interaction with cysteine in the cFos DNA-binding domain: implications for chemoprevention of UVB-induced skin cancer.
Cancer Res. 2009 Sep 1;69(17):7103-10. Epub 2009 Aug 11.
Dickinson SE, Melton TF, Olson ER, Zhang J, Saboda K, Bowden GT.
Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724, USA.
Sulforaphane is an isothiocyanate derived from cruciferous vegetables that has been linked to decreased risk of certain cancers. Although the role of sulforaphane in the induction of the transcription factor Nrf2 has been studied extensively, there is also evidence that inhibition of the transcription factor activator protein-1 (AP-1) may contribute to the chemopreventive properties of this compound. In this study, we show for the first time that sulforaphane is effective at reducing the multiplicity and tumor burden of UVB-induced squamous cell carcinoma in a mouse model using cotreatment with the compound and the carcinogen. We also show that sulforaphane pretreatment is able to reduce the activity of AP-1 luciferase in the skin of transgenic mice after UVB. Chromatin immunoprecipitation analysis verified that a main constituent of the AP-1 dimer, cFos, is inhibited from binding to the AP-1 DNA binding site by sulforaphane. Electrophoretic mobility shift assay analysis of nuclear proteins also shows that sulforaphane and diamide, both known to react with cysteine amino acids, are effective at inhibiting AP-1 from binding to its response element. Using truncated recombinant cFos and cJun, we show that mutation of critical cysteines in the DNA-binding domain of these proteins (Cys(154) in cFos and Cys(272) in cJun) results in loss of sensitivity to both sulforaphane and diamide in electrophoretic mobility shift assay analysis. Together, these data indicate that inhibition of AP-1 activity may be an important molecular mechanism in chemoprevention of squamous cell carcinoma by sulforaphane.
Note from ISS: Several crucifer sprouts including broccoli sprouts are currently the most potent natural source of sulforaphane known. They often produce 10 to 100 times the amount of sulforaphane as their corresponding mature vegetables.
“Broccoli sprouts have a very high concentration of sulforaphane since this compound originates in the seed and is not made in the plant as it grows. One sprout contains all of the sulforaphane that is present in a full grown broccoli plant.”
“Nutrition and cancer: a review of the evidence for an anti-cancer diet” Nutr J. 2004 Oct 20;3:19, Donaldson MS. Hallelujah Acres Foundation, 13553 Vantage Hwy, Ellensburg, WA 98926, USA.