JNK and p53 stress signaling cascades are altered in MCF-7 cells resistantto tumor necrosis factor-mediated apoptosis

Tumor necrosis factor (TNF) signal transduction is a complex process involv ing activation of receptor-linked and stress-sensitive signaling cascades t hat stimulate apoptosis in some tumor cell lines. Initial studies suggested that these signaling events cooperatively induced TNF responses, but recen t studies suggest that some of these signals antagonize the apoptotic respo nse or play no discernible role in cell death. As TNF induces cellular stre ss and activates several stress-sensitive cascades that may play a role in apoptosis, TNF-induced stress signaling was examined in MCF-7 cells and com pared with a variant MCF-7 cell line resistant to TNF-mediated apoptosis (M CF-7/3E9), TNF rapidly stimulated both NF-kappa B and JNK activation in MCF -7 and MCF-7/3E9 cells, but JNK activation was significantly reduced (three fold) in apoptotically resistant cells. TNF also stimulated p53, p21WAF1, a nd Bar accumulation with subsequent PARP cleavage and nucleosomal DNA ladde ring in MCF-7 cells but did not stimulate these processes in MCF-7/3E9 cell s. Importantly, 3E9 cells retained wild-type p53 function, induced p21WAF1 in response to DNA damage, and expressed almost equal sensitivity to other stress stimuli (gamma-radiation, chemotherapeutic agents) as parental MCF-7 cells. These results suggest that selective defects in TNF-activated stres s cascades are associated with reduced sensitivity to TNF but not other cel l death stimuli. Loss of potent TNF-mediated activation of JNK and p53 casc ades may permit tumor cells to evade receptor-mediated apoptosis but have o nly limited influence on cellular sensitivity to other agents that effectiv ely engage these stress pathways.