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

We have compared several breast cancer cell lines that differ in their resp onsiveness to TNF to determine the involvement of PKC isozymes in regulatin g sensitivity of breast cancer cells to TNF. While MCF-7 and BT-20 cells we re responsive to TNF without any metabolic inhibitors, CAMA-1 and SKBR-3 ce lls responded to TNF in the presence of cycloheximide; MDA-MB-231 and Hs578 t cells were resistant to TNF even in the presence of cycloheximide. Bisind olylmaleimide (BIM), an inhibitor of PKC, either alone (MCF-7 and BT-20) or in combination with cycloheximide enhanced sensitivity of these cells to T NF. The PKC isozyme profile of MCF-7 cells was similar to BT-20 cells and t hat of CAMA-1 cells was similar to SKBR-3 cells. MCF-7, BT-20 and MDA-MB-23 1 cells that were most responsive to BIM-mediated sensitization to TNF cont ained relatively high level of PKC epsilon and proteolytic cleavage of PKC epsilon correlated with TNF-induced cell death. BIM did not inhibit NF-kapp aB activation by TNF but caused activation of caspases and enhanced cleavag e of PKC delta and -epsilon. These results suggest that proteolytic cleavag e of PKC epsilon may be associated with PKC inhibitor mediated sensitizatio n of breast cancer cells to TNF. (C) 2001 Academic Press.