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. Gemcitabine treatment decreased the expression of IkappaB-alpha protein and, concomitantly, increased the activity of nuclear factor-kappaB (NF-kappaB) transcription factor, a known inhibitor of the apoptotic response. This increase 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, since overexpression of a dominant negative version of IkappaB-alpha, which suppresses NF-kappaB activation, blocks the increase of IAP-1 protein and potentiates the action of gemcitabine. Additionally, overexpression of IAP-1 protein in A549 cells expressing the IkappaB-alpha mutant restored the initial sensitivity to gemcitabine and demonstrated that this protein was responsible 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.
Bandala
E
E
Laboratorio de Biologiá Molecular, División de Investigación Básica, Instituto Nacional de Cancerología, Av. San Fernando 22, Tlalpan 14000, Mexico City, D.F., Mexico.
Espinosa
M
M
Maldonado
V
V
Meléndez-Zajgla
J
J
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology*; D029721:Drosophila Proteins; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D019476:Insect Proteins / Q000096:biosynthesis* / Q000502:physiology; D008175:Lung Neoplasms; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; C111891:DIAP1 protein, Drosophila; D029721:Drosophila Proteins; D051034:Inhibitor of Apoptosis Proteins; D019476:Insect Proteins; D003841:Deoxycytidine; D000093542:Gemcitabine