Roles of NF-κB 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, Ram Ganapathi

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

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 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 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/G 2 + 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.

Original languageEnglish
Pages (from-to)8029-8036
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number11
DOIs
Publication statusPublished - Mar 16 2001
Externally publishedYes

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irinotecan
Type II DNA Topoisomerase
Type I DNA Topoisomerase
Poisons
Cell death
Proteasome Endopeptidase Complex
Etoposide
Cell Death
Cells
Apoptosis
Carcinoma
Lung
Chemical activation
Proteasome Inhibitors
DNA Damage
DNA
Effector Caspases
Caspase 7
Poly(ADP-ribose) Polymerases
Caspase 9

ASJC Scopus subject areas

  • Biochemistry

Cite this

Roles of NF-κB and 26 S Proteasome in Apoptotic Cell Death Induced by Topoisomerase I and II Poisons in Human Nonsmall Cell Lung Carcinoma. / Tabata, Masahiro; Tabata, Rika; Grabowski, Dale R.; Bukowski, Ronald M.; Ganapathi, Mahrukh K.; Ganapathi, Ram.

In: Journal of Biological Chemistry, Vol. 276, No. 11, 16.03.2001, p. 8029-8036.

Research output: Contribution to journalArticle

Tabata, Masahiro ; Tabata, Rika ; Grabowski, Dale R. ; Bukowski, Ronald M. ; Ganapathi, Mahrukh K. ; Ganapathi, Ram. / Roles of NF-κB and 26 S Proteasome in Apoptotic Cell Death Induced by Topoisomerase I and II Poisons in Human Nonsmall Cell Lung Carcinoma. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 11. pp. 8029-8036.
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abstract = "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 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 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/G 2 + 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.",
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