Potential attenuation of p38 signaling by DDB2 as a factor in acquired TNF resistance

Our previous study demonstrated that DDB2, a DNA repair protein, attenuates cell surface membrane-associated death signal induced by UV or FasAb; DDB2 is overexpressed in cisplatin-selected cells. However, the molecular mechanism underlying the protective role of DDB2 along the apoptotic pathway remains unknown. Our study identified the cross-resistance of the cisplatin-selected cells to tumor necrosis factor-α (TNF-α). Since knock-down of the DDB2 level rendered cells (HR18) sensitive to the treatment, the cell sensitivity to TNF-α appears inversely proportional to the cellular level of DDB2. Treatment of HeLa cells with TNF-α transiently induced activation of p38MAPK signal, but this induction was significantly reduced in the resistant cells. Overexpression of DDB2 attenuated the activation of p38 in cells. TNF-α-induced apoptotic signals, represented by caspase-8 and downstream substrate cleavage, were reduced in resistant cells compared to their sensitive counterparts. Inhibition of p38 signal by SB202190 clearly attenuated TNF-α-induced apoptotic signals. Moreover, over-expression of DDB2 in HR18 cells also attenuated TNF-α induced caspase activation. These results suggest that p38MAPK activation may be a key upstream signal of TNF-α-induced apoptosis and that attenuation of p38 signal by DDB2 overexpression may be responsible for acquired TNF-α resistance.