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J. Biol. Chem., Vol. 283, Issue 20, 13736-13744, May 16, 2008

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Fhit Interaction with Ferredoxin Reductase Triggers Generation of Reactive Oxygen Species and Apoptosis of Cancer Cells^*

Francesco Trapasso¹, Flavia Pichiorri^¶1, Marco Gaspari, Tiziana Palumbo^||, Rami I. Aqeilan, Eugenio Gaudio, Hiroshi Okumura, Rodolfo Iuliano, Giampiero Di Leva, Muller Fabbri, David E. Birk^**, Cinzia Raso, Kari Green-Church, Luigi G. Spagnoli^¶, Salvatore Venuta, Kay Huebner, and Carlo M. Croce²

From the Ohio State University, Comprehensive Cancer Center, Columbus, Ohio 43210, the Dipartimento di Medicina Sperimentale e Clinica, University "Magna Græcia" of Catanzaro, 88100 Catanzaro, Italy, the ^¶Istituto di Anatomia Patologica, University "Tor Vergata" of Rome, 00173 Rome, Italy, the ^||Dipartimento di Farmacologia Sperimentale Preclinica e Clinica, University of Catania, 95123 Catania, Italy, and the ^**Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Fhit protein is lost in most cancers, its restoration suppresses tumorigenicity, and virus-mediated FHIT gene therapy induces apoptosis and suppresses tumors in preclinical models. We have used protein cross-linking and proteomics methods to characterize a Fhit protein complex involved in triggering Fhit-mediated apoptosis. The complex includes Hsp60 and Hsp10 that mediate Fhit stability and may affect import into mitochondria, where it interacts with ferredoxin reductase, responsible for transferring electrons from NADPH to cytochrome P450 via ferredoxin. Viral-mediated Fhit restoration increases production of intracellular reactive oxygen species, followed by increased apoptosis of lung cancer cells under oxidative stress conditions; conversely, Fhit-negative cells escape apoptosis, carrying serious oxidative DNA damage that may contribute to an increased mutation rate. Characterization of Fhit interacting proteins has identified direct effectors of the Fhit-mediated apoptotic pathway that is lost in most cancers through loss of Fhit.

Received for publication, November 5, 2007 , and in revised form, February 28, 2008.

This paper is dedicated to the memory of Salvatore Venuta, Chief of the University of Catanzaro and eminent oncologist, who died prematurely on April 3, 2007.

^* This work was supported, in whole or in part, by National Institutes of Health Grants CA77738 and CA78890. This work was also supported by the Associazione Italiana Ricerca Cancro. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Methods and Figs. S1–S3.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: BRT Rm. 1082, 460 W. 12th Ave., Columbus, OH 43210. Tel.: 614-292-4930; Fax: 614-292-3558; E-mail: Carlo.Croce{at}osumc.edu.