α-Tocopheryl succinate inhibits malignant mesothelioma by disrupting the Fibroblast Growth Factor Autocrine Loop: Mechanism and the role of oxidative stress
MetadataShow full item record
We have studied the potential effect against human malignant mesotheliomas (MM) of a-tocopheryl succinate (a-TOS), a redox-silent vitamin E analog with strong pro-apoptotic and anti-cancer activity. a-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 a-TOS on genes playing a major role in MM progression. Of these, a-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 a-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 ofMMcell proliferation by a-TOS as well as a-TOS-induced inhibition of egr-1-dependent transactivation. Finally, a-TOS significantly suppressed experimental MM in immunocompromised mice. Our data suggest that a-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.
Journal of Biological Chemistry
Copyright 2005 American Society for Biochemistry and Molecular Biology. Reproduced in accordance with the copyright policy of the publisher. This journal is available online, use hypertext links.