Ferritin is a protein with a pivotal role in the protection against oxidative stress. Due to its ability to sequester iron, ferritin reduces the availability of iron to catalytically generate oxygen free radicals through Fenton chemistry. Consistent with this protective role, the investigators have recently observed that ferritin is transcriptionally-induced in response to oxidative stress, and that ferritin overexpression can substantially dampen free radicals generated in response to exogenous stress stimuli. The response of ferritin is mediated by a cis-acting element, the antioxidant response element (ARE, also called EpRE or OSRE). The ARE is also found in other cytoprotective proteins, such as the gluthatione-S-transferases, heme oxygenase, gamma glutamyl cysteine synthetase, NAD(P)H quinone oxidoreductase and others. These enzymes constitute the so-called Phase II response. The investigators' observations therefore link ferritin and hence iron biology to this antioxidant cytoprotective response, and suggest that ferritin might play a role in the cytoprotective action of chemopreventive agents. They further suggest that dietary nutrients that induce the phase II response will induce ferritin. The preliminary results show that this is in fact the case: curcumin, a natural chemopreventive agent found in turmeric, curry and mustard, induces ferritin in vitro. The overall hypothesis to be tested in this proposal is that ferritin plays a role in the protection against oxidative stress and oxidative stress-induced tumorigenesis mediated by the dietary nutrient curcumin.
The Specific Aims are to: (1) Characterize the effect of curcumin on ferritin. Mice will be fed diets containing curcumin, and the response of ferritin compared to that of other Phase II proteins will be assessed. The relationship between ferritin induction, oxidative stress, and tumor formation in mice will be assessed. (2) Isolate and evaluate the contribution of ferritin induction to the overall cytoprotective response induced by curcumin. Cells will be treated with curcumin, and their response to oxidative challenge assessed. The role of ferritin induction in oxidative stress protection will be tested by selectively blocking ferritin induction. The investigators will also test whether protection afforded by curcumin can be recapitulated by overexpression of ferritin. Over the long term, the studies may suggest practical nutritional intervention strategies for the reduction of oxidative stress through nutritional modulation of ferritin.
|Jiao, Yan; Wilkinson 4th, John; Christine Pietsch, E et al. (2006) Iron chelation in the biological activity of curcumin. Free Radic Biol Med 40:1152-60|
|Pietsch, E Christine; Hurley, Allison L; Scott, Elizabeth E et al. (2003) Oxathiolene oxides: a novel family of compounds that induce ferritin, glutathione S-transferase, and other proteins of the phase II response. Biochem Pharmacol 65:1261-9|