Activation of NF-kappa B determines the sensitivity of human colon cancer cells to TNF alpha-induced apoptosis

Tumor necrosis factor alpha (TNF alpha) generates a potent cytotoxic effect , however many cancer cells are resistant to TNF alpha-mediated killing and the cause of the differential sensitivity remains to he elucidated. In thi s study, we demonstrated that TNF alpha induced cell death in four differen t human colon cancer cell lints. The degree of cytotoxic effect was differe nt in each cell line, in that HCT-15 was relatively sensitive, while DLD-1, HT-29 and WiDr were relatively resistant. TNF alpha induced apoptotic chan ges such as morphological changes, DNA fragmentation and activation of casp ase-3 in HCT-15, but to a lesser degree in the others. Transcriptional expr ession of TNFR1(p55), as well as that of FLICE, Fas, FADD, DR3, FAF, TRADD, and RIP was similar in these cell lines, indicating that the susceptibilit y to TNF alpha-induced apoptosis may not be determined by the constitutive expression level of these factors. Interestingly, the cytotoxic effect of T NF alpha was well correlated with the DNA binding activity of NF-kappa B in the colon cancer cell lines. Further, the overexpression of a non-phosphor ylated mutant form of I kappa B alpha enhanced the cytotoxicity of TNF alph a in the resistant cell line, DLD-1, indicating that NF-kappa B activity ma y determine the sensitivity of colon cancer cells to TNF alpha-induced apop tosis, Thus, our results indicate that modulation of NF-kappa B activity ma y provide a useful tool to sensitize colon cancer cells to TNF alpha treatm ent.