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Originally published In Press as doi:10.1074/jbc.M009831200 on December 13, 2000

J. Biol. Chem., Vol. 276, Issue 11, 8029-8036, March 16, 2001
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Roles of NF-kappa B and 26 S Proteasome in Apoptotic Cell Death Induced by Topoisomerase I and II Poisons in Human Nonsmall Cell Lung Carcinoma*

Masahiro Tabata, Rika Tabata, Dale R. Grabowski, Ronald M. Bukowski, Mahrukh K. Ganapathi, and Ram GanapathiDagger

From the Experimental Therapeutics Program, Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio 44195

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-kappa B before induction of apoptosis. Inhibiting the degradation of Ikappa Balpha by pretreatment with the proteasome inhibitor MG-132 significantly inhibited NF-kappa B 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 Ikappa Balpha (mIkappa Balpha ) inhibited SN-38 or VP-16 induced transcription and DNA binding activity of NF-kappa B without altering drug-induced apoptosis. Regulation of apoptosis by mitochondrial release of cytochrome c and activation of pro-caspase 9 followed by cleavage of poly(ADP-ribose) polymerase by effector caspases 3 and 7 was similar in neo and mIkappa Balpha 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 mIkappa Balpha 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-kappa B but can be manipulated by proteasome inhibitors.

* This work was supported by United States Public Health Service Grants RO1 CA35531 and RO1 CA74939 and an educational/research grant from Rodney A. Beason, Medical Sciences Liaison Oncology, Medical Operations and Scientific Affairs, Pharmacia & Upjohn.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Taussig Cancer Center, R40, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-444-2085; Fax: 216-444-7115; E-mail: ganapar@ cc.ccf.org.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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