Iron-Dependent Regulation of MDM2 Influences p53 Activity and Hepatic Carcinogenesis

Abstract

Iron overload is a risk factor for hepatocarcinoma, but the pathways involved are poorly characterized. Gene expression analysis in immortalized mouse hepatocytes exposed to iron or the iron chelator deferoxamine revealed that iron downregulated, whereas deferoxamine upregulated, mRNA levels of mouse double minute gene 2 (MDM2), the ubiquitin ligase involved in the degradation of the oncosuppressor p53. Regulation of MDM2 by iron status was observed at protein levels in mouse hepatocytes and rat liver, and was associated with specular changes in p53 expression. Iron dependent regulation of MDM2/ p53 was confirmed ex-vivo in human monocytes, by manipulation of iron pool and in a genetic model of iron deficiency, leading to modulation of p53 target genes involved in the antioxidant response and apoptosis. Iron status influenced p53 ubiquitination and degradation rate, and the MDM2 inhibitor nutlin increased p53 levels in iron-depleted cells. Furthermore, nutlin enhanced the antiproliferative activity of deferoxamine in HepG2 hepatoblastoma cells. The MDM2 ؊309T > G promoter polymorphism, determining increased MDM2 and lower p53 activity, was associated with higher risk of hepatocarcinoma in cirrhotic patients with hemochromatosis, and with HFE mutations in patients with hepatocarcinoma without hemochromatosis, suggesting an interaction between MDM2 and iron in the pathogenesis of hepatocarcinoma. In conclusion, iron status influences p53 activity and antioxidant response by modulating MDM2 expression. MDM2 inhibitors may enhance the antiproliferative activity of iron chelators. (Am J Pathol

Role of iron in hepatocellular carcinoma

“…Reactive oxygen species production, in physiologic conditions controlled by antioxidant intracellular defense mechanisms, can lead to lipid peroxidation and oxidative damage to several cellular membranes and organelles, including DNA. Thus, excess free iron with reactive oxygen species overproduction in hepatic tissue, exceeding the cellular defenses, could be responsible for mutagenesis and hepatocarcinogenesis, overcoming the protective effect of activation of tumor suppressor genes and critical DNA repair genes orchestrated by p53 [5][6][7] (Fig. 1).…”

Ferredoxin reductase is critical for p53-dependent tumor suppression via iron regulatory protein 2

“…p53 transcriptional activity is also modulated by cellular redox state and the abundance of ADP and iron in response to altered energy and iron metabolism (Vogelstein et al 2000;Abeysinghe et al 2001;Liang and Richardson 2003;Whitnall et al 2006;Yang et al 2006;Kawauchi et al 2008;Dongiovanni et al 2010;PuzioKuter 2011;Shen et al 2014). Upon activation, p53 induces a plethora of genes for prosurvival (such as p21), proapoptotic (such as Puma), and many other biological responses (Riley et al 2008;Vousden and Prives 2009).…”

Association Between MDM2 Promoter SNP309 T/G Polymorphism and Liver Cancer Risk - a Meta-analysis

“…This increase in MDM2 results in the direct inhibition of p53 transcriptional activity, enabling damaged cell to escape the cell-cycle checkpoint and become carcinogenic (Dongiovanni et al, 2010;Embade et al, 2012). Overexpression of MDM2 by up to four-fold in transgenic mice harboring wild-type p53 can lead to carcinogenesis (Stommel and Wahl, 2005;Gajjar et al, 2012).…”