Restoration of miR-34a in p53 deficient cells unexpectedly promotes the cell survival by increasing NFκB activity

Abstract

Upregulation of miR-34a by p53 is recently believed to be a key mediator in the pro-apoptotic effects of this tumor suppressor. We sought to determine whether restoration of miR-34a levels in p53 deficient cells could rescue the response to DNA damage. Compared with the p53 wildtype U2OS cells, miR-34a expression was much lower in p53 deficient Saos2 cells upon cisplatin treatment. Unexpectedly, delivery of miR-34a in Saos2 cells does not increase the cell sensitivity to apoptosis. This effect was mediated by direct downregulation of SirT1 expression by miR-34a, which in turn increased the NFκB activity. Inhibition of NFκB activity in Saos2 cells by Aspirin sensitized the miR-34a overexpressing cells to cell death. Thus, in tumors with p53 deficiency, miR-34a restoration alone confers drug resistance through Sirt1-NFκB pathway and combination of miR-34a and NFκB inhibitor could be considered as a promising therapeutic strategy.