| Autor: |
Tabata, Masahiro, Tabata, Rika, Grabowski, Dale R., Bukowski, Ronald M., Ganapathi, Mahrukh K., Ganapathi, Ram |
| Zdroj: |
Journal of Biological Chemistry; March 2001, Vol. 276 Issue: 11 p8029-8036, 8p |
| Abstrakt: |
Activation of signaling pathways after DNA damage induced by topoisomerase (topo) poisons can lead to cell death by apoptosis. Treatment of human nonsmall cell lung carcinoma (NSCLC-3 or NSCLC-5) cells with the topo I poison SN-38 or the topo II poison etoposide (VP-16) leads to activation of NF-κB before induction of apoptosis. Inhibiting the degradation of IκBα by pretreatment with the proteasome inhibitor MG-132 significantly inhibited NF-κB activation and apoptosis but not DNA damage induced by SN-38 or VP-16. Transfection of NSCLC-3 or NSCLC-5 cells with dominant negative mutant IκBα (mIκBα) inhibited SN-38 or VP-16 induced transcription and DNA binding activity of NF-κB without altering drug-induced apoptosis. Regulation of apoptosis by mitochondrial release of cytochrome cand activation of pro-caspase 9 followed by cleavage of poly(ADP-ribose) polymerase by effector caspases 3 and 7 was similar in neo and mIκBα cells treated with SN-38 or VP-16. In contrast to pretreatment with MG-132, exposure to MG-132 after SN-38 or VP-16 treatment of neo or mIκBα cells decreased cell cycle arrest in the S/G2+ M fraction and enhanced apoptosis compared with drug alone. In summary, apoptosis induced by topoisomerase poisons in NSCLC cells is not mediated by NF-κB but can be manipulated by proteasome inhibitors. |
| Databáze: |
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