Inhibitor of apoptosis-1 (IAP-1) expression and apoptosis in non-small-cell lung cancer cells exposed to gemcitabine

Exposure of lung cancer cells to gemcitabine (2',2'-difluorodeoxycytidine) arrests cells in S phase and induces secondary apoptotic cell death. Gemcit abine treatment decreased the expression of I kappaB-alpha protein and, con comitantly, increased the activity of nuclear factor-kappaB (NF-kappaB) tra nscription factor, a known inhibitor of the apoptotic response. This increa se was accompanied by a similar increment in the expression of inhibitor of apoptosis-1 (IAP-1) protein and mRNA, a caspase inhibitor responsive to NF -kappaB. These changes were important to the final destiny of the cells, si nce overexpression of a dominant negative version of I kappaB-alpha, which suppresses NF-kappaB activation, blocks the increase of IAP-1 protein and p otentiates the action of gemcitabine. Additionally, overexpression of IAP-1 protein in A549 cells expressing the I kappaB-alpha mutant restored the in itial sensitivity to gemcitabine and demonstrated that this protein was res ponsible for the inhibitory effect of NF-kappaB. These results support the notion of IAP-1 as an important antiapoptotic protein mediating sensitivity to deoxynucleotides analogs in non-small-cell lung cancer cells. (C) 2001 Elsevier Science Inc. All rights reserved.