Differential sensitivity of breast cancer cells to tumor necrosis factor-α: Involvement of protein kinase C

We have compared several breast cancer cell lines that differ in their responsiveness to TNF to determine the involvement of PKC isozymes in regulating sensitivity of breast cancer cells to TNF. While MCF-7 and BT-20 cells were responsive to TNF without any metabolic inhibitors, CAMA-1 and SKBR-3 cells responded to TNF in the presence of cycloheximide; MDA-MB-231 and Hs578t cells were resistant to TNF even in the presence of cycloheximide. Bisindolylmaleimide (BIM), an inhibitor of PKC, either alone (MCF-7 and BT-20) or in combination with cycloheximide enhanced sensitivity of these cells to TNF. The PKC isozyme profile of MCF-7 cells was similar to BT-20 cells and that of CAMA-1 cells was similar to SKBR-3 cells. MCF-7, BT-20 and MDA-MB-231 cells that were most responsive to BIM-mediated sensitization to TNF contained relatively high level of PKCε and proteolytic cleavage of PKCε correlated with TNF-induced cell death. BIM did not inhibit NF-κB activation by TNF but caused activation of caspases and enhanced cleavage of PKCδ and -ε. These results suggest that proteolytic cleavage of PKCε may be associated with PKC inhibitor mediated sensitization of breast cancer cells to TNF.