HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 48, 50455-50464, November 26, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/48/50455    most recent M406749200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Qanungo, S. Articles by Nieminen, A.-L. Search for Related Content PubMed PubMed Citation Articles by Qanungo, S. Articles by Nieminen, A.-L. Social Bookmarking                      What's this?

N-Acetyl-L-cysteine Enhances Apoptosis through Inhibition of Nuclear Factor-B in Hypoxic Murine Embryonic Fibroblasts^*

Suparna Qanungo, Mi Wang, and Anna-Liisa Nieminen

From the Department of Anatomy and Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106

In this study, we investigated the role of reduced glutathione (GSH) and nuclear factor-B (NFB) in hypoxia-induced apoptosis. Hypoxia caused p53-dependent apoptosis in murine embryonic fibroblasts transfected with Ras and E1A. N-Acetyl-L-cysteine (NAC) but not other antioxidants, such as the vitamin E analog trolox and epigallocatechin-3-gallate, enhanced hypoxia-induced caspase-3 activation and apoptosis. NAC also enhanced hypoxia-induced apoptosis in two human cancer cell lines, MIA PaCa-2 pancreatic cancer cells and A549 lung carcinoma cells. In murine embryonic fibroblasts, all three antioxidants blocked hypoxia-induced reactive oxygen species formation. NAC did not enhance hypoxia-induced cytochrome c release but did enhance poly-(ADP ribose) polymerase cleavage, indicating that NAC acted at a post-mitochondrial level. NAC-mediated enhancement of apoptosis was mimicked by incubating cells with GSH monoester, which increased intracellular GSH similarly to NAC. Hypoxia promoted degradation of an inhibitor of B(IB), NFB-p65 translocation into the nucleus, NFB binding to DNA, and subsequent transactivation of NFB, which increased X chromosome-linked inhibitor of apoptosis protein levels. NAC failed to block degradation by IB and sequestration of the p65 subunit of NFB to the nucleus. However, NAC did abrogate hypoxia-induced NFB binding to DNA, NFB-dependent gene expression, and induction of X chromosome-linked inhibitor of apoptosis protein. In conclusion, NAC enhanced hypoxic apoptosis by a mechanism apparently involving GSH-dependent suppression of NFB transactivation.

Received for publication, June 16, 2004 , and in revised form, August 19, 2004.

^* This research was supported by Grants RO1 NS39469 and P30 CA 43703. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Case Comprehensive Cancer Center Laboratories, Case Western Reserve University, 3-134 Wolstein Research Bldg., 10900 Euclid Ave., Cleveland, OH 44106-7285. Tel.: 216-368-5680; Fax: 216-368-8919; E-mail: axn25{at}case.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				G. W. Tew, E. L. Lorimer, T. J. Berg, H. Zhi, R. Li, and C. L. Williams SmgGDS Regulates Cell Proliferation, Migration, and NF-{kappa}B Transcriptional Activity in Non-small Cell Lung Carcinoma J. Biol. Chem., January 11, 2008; 283(2): 963 - 976. [Abstract] [Full Text] [PDF]

				M. Martinez-Losa, J. Cortijo, G. Juan, M. Ramon, M. J. Sanz, and E. J. Morcillo Modulatory effects of N-acetyl-L-cysteine on human eosinophil apoptosis Eur. Respir. J., September 1, 2007; 30(3): 436 - 442. [Abstract] [Full Text] [PDF]

				S. Qanungo, D. W. Starke, H. V. Pai, J. J. Mieyal, and A.-L. Nieminen Glutathione Supplementation Potentiates Hypoxic Apoptosis by S-Glutathionylation of p65-NF{kappa}B J. Biol. Chem., June 22, 2007; 282(25): 18427 - 18436. [Abstract] [Full Text] [PDF]

				D. N. Criddle, S. Gillies, H. K. Baumgartner-Wilson, M. Jaffar, E. C. Chinje, S. Passmore, M. Chvanov, S. Barrow, O. V. Gerasimenko, A. V. Tepikin, et al. Menadione-induced Reactive Oxygen Species Generation via Redox Cycling Promotes Apoptosis of Murine Pancreatic Acinar Cells J. Biol. Chem., December 29, 2006; 281(52): 40485 - 40492. [Abstract] [Full Text] [PDF]

				M. F. McCarty and K. I. Block Preadministration of High-Dose Salicylates, Suppressors of NF-{kappa}B Activation, May Increase the Chemosensitivity of Many Cancers: An Example of Proapoptotic Signal Modulation Therapy Integr Cancer Ther, September 1, 2006; 5(3): 252 - 268. [Abstract] [PDF]

				W. Matsuyama, M. Watanabe, Y. Shirahama, H. Mitsuyama, I. Higashimoto, M. Osame, and K. Arimura Discoidin Domain Receptor 1 Contributes to the Survival of Lung Fibroblast in Idiopathic Pulmonary Fibrosis Am. J. Pathol., March 1, 2006; 168(3): 866 - 877. [Abstract] [Full Text] [PDF]

				D. M. Flaherty, M. M. Monick, and S. L. Hinde Human Alveolar Macrophages Are Deficient in PTEN: THE ROLE OF ENDOGENOUS OXIDANTS J. Biol. Chem., February 24, 2006; 281(8): 5058 - 5064. [Abstract] [Full Text] [PDF]