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-alpha (TNF-alpha). Since knock-down of the DDB2 level rendered cells (HR18) sensitive to the treatment, the cell sensitivity to TNF-alpha appears inversely proportional to the cellular level of DDB2. Treatment of HeLa cells with TNF-alpha 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-alpha-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-alpha-induced apoptotic signals. Moreover, overexpression of DDB2 in HR18 cells also attenuated TNF-alpha induced caspase activation. These results suggest that p38MAPK activation may be a key upstream signal of TNF-alpha-induced apoptosis and that attenuation of p38 signal by DDB2 overexpression may be responsible for acquired TNF-alpha resistance.
Sun
Chun-Ling
CL
Tumor Biology Laboratory, Department of Biochemistry, Chang Gung University, Taoyuan, Taiwan.
Chao
Chuck C-K
CC
D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002945:Cisplatin / Q000009:adverse effects; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects*; D014983:Xeroderma Pigmentosum; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020169:Caspases; D002945:Cisplatin