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Bak

A Downstream Mediator of Fenretinide-Induced Apoptosis of SH-SY5Y Neuroblastoma Cells¹

Northern Institute for Cancer Research, University of Newcastle Upon Tyne, Newcastle Upon Tyne NE2 4HH, United Kingdom, [P. E. L., B. G., C. P. F. R.]; Department of Biology, University of Rome Tor Vergata, Rome, 00133, Italy [S. O., C. R.]; Istituto Dermatopatico Immacolata–Istituto per Ricovero per la Cura a Carattere Scientifico Biochemistry Laboratory, Department of Experimental Medicine, University of Rome Tor Vergata, Rome, 00133, Italy [M. R., G. M.]; and Istituto Nazionale per la Malattie Infettive–Istituto per Ricovero per la Cura a Carattere Scientifico Lazzaro Spallanzani, Rome, 00149, Italy [M. C., M. P.]

Unlike 13-cis-retinoic acid, the synthetic retinoid fenretinide [N-(4-hydroxyphenyl)retinamide] induces apoptosis of neuroblastoma cells by mechanisms involving retinoic acid receptors and oxidative stress. After screening a cDNA array for apoptosis-related genes, the Bcl2-related protein Bak was identified as a fenretinide-inducible gene in SH-SY5Y neuroblastoma cells, and this was confirmed by Western blotting and flow cytometry. Although fenretinide acts synergistically in vitro with chemotherapeutic drugs, these drugs did not induce Bak expression. Retinoic acid receptor antagonists did not block the induction of Bak by fenretinide. Conversely, Bak induction was blocked by the antioxidant vitamin C. Overexpression of Bak increased apoptosis in both the presence and absence of fenretinide, whereas expression of antisense Bak inhibited fenretinide-induced apoptosis. Bak expression was also induced in cells overexpressing the stress-induced transcription factor GADD153, but Bak expression was inhibited in cells expressing an antisense GADD153 construct. These results suggest that Bak is a downstream mediator of an oxidative stress pathway leading to apoptosis of SH-SY5Y neuroblastoma cells in response to fenretinide.

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