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J. Biol. Chem., Vol. 280, Issue 27, 25369-25376, July 8, 2005

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-Tocopheryl Succinate Inhibits Malignant Mesothelioma by Disrupting the Fibroblast Growth Factor Autocrine Loop

MECHANISM AND THE ROLE OF OXIDATIVE STRESS^*

Michael Stapelberg, Nina Gellert, Emma Swettenham, Marco Tomasetti¶, Paul K. Witting||, Antonio Procopio¶, and Jiri Neuzil**

From the Apoptosis Research Group, School of Medical Science, Griffith University, Southport, 4216 Queensland, Australia, the ^¶Department of Molecular Pathology, Polytechnic University of Marche, Ancona 60131, Italy,^|| ANZAC Institute, Concorde Hospital, University of Sydney, Concord 2139, New South Wales, Australia, and^** Laboratory of Apoptosis and Cell Signalling, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague 14220, Czech Republic

We have studied the potential effect against human malignant mesotheliomas (MM) of -tocopheryl succinate (-TOS), a redox-silent vitamin E analog with strong pro-apoptotic and anti-cancer activity. -TOS at sub-apoptotic levels inhibited proliferation of MM cell lines, while being nontoxic to nonmalignant mesothelial cells. Because MM cells are typified by a highly metastatic phenotype, we investigated the effect of -TOS on genes playing a major role in MM progression. Of these, -TOS down regulated fibroblast growth factor (FGF)-1 and, in particular, FGF-2 on the transcriptional level in MM cells, and this was not observed in their nonmalignant counterparts. FGF-2 short interfering RNA suppressed proliferation of MM cells. Down-regulation of FGF-2 was likely because of inhibition of the egr-1 transcription activity that was decreased in MM cells via oxidative stress induced by -TOS, as evidenced by EPR spectroscopy, whereas nonmalignant cells did not show this response. Treatment of MM cells with egr-1 short interfering RNA suppressed proliferation, which was overridden by exogenously added recombinant FGF-1 and, in particular, FGF-2. An analog of coenzyme Q targeted to mitochondria and superoxide dismutase overrode inhibition of MM cell proliferation by -TOS as well as -TOS-induced inhibition of egr-1-dependent transactivation. Finally, -TOS significantly suppressed experimental MM in immunocompromised mice. Our data suggest that -TOS suppresses MM cell proliferation by disrupting the FGF-FGF receptor autocrine signaling loop by generating oxidative stress and point to the agent as a selective drug against thus far fatal mesotheliomas.

Received for publication, December 23, 2004 , and in revised form, April 28, 2005.

^* This work was supported in part by grants from the Dust Diseases Board of Australia, the Queensland Cancer Fund, the Australian Research Council Discovery grant, Project AV0Z5052014 from the Academy of Sciences of the Czech Republic (to J. N.), and by an Australian Research fellowship (to P. K. W.). 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.

Present address: Dept. of Dermatology, School of Medicine, University of Sydney, Sydney 2000, New South Wales, Australia.

To whom correspondence should be addressed: Apoptosis Research Group, Heart Foundation Research Centre, School of Medical Science, Griffith University Gold Coast Campus, Southport, 4216 Queensland, Australia. Tel.: 61-7-555-29109; Fax: 61-7-555-28444; E-mail: j.neuzil{at}griffith.edu.au.

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