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(American Journal of Pathology. 2002;161:2229-2240.)
© 2002 American Society for Investigative Pathology

Regular Articles

Constitutive Nuclear Factor-{kappa}B Activity Is Crucial for Human Retinoblastoma Cell Viability

Vassiliki Poulaki*, Constantine S. Mitsiades{dagger}, Antonia M. Joussen{ddagger}§, Alexandra Lappas{ddagger}§, Bernd Kirchhof{ddagger}§ and Nicholas Mitsiades{dagger}

From the Retina Research Laboratory,* Massachusetts Eye and Ear Infirmary, and the Dana-Farber Cancer Institute,{dagger} Harvard Medical School, Boston, Massachusetts; and the Department of Vitreoretinal Surgery,{ddagger} Center for Ophthalmology, and the Center for Molecular Medicine (Zentrum für Molekulare Medizin),§ University of Cologne, Köln, Germany

Retinoblastoma (Rb) is the most common intraocular malignancy of childhood. Although systemic and intrathecal chemotherapy with local and cranial radiotherapy have improved overall survival, the prognosis for patients with central nervous system involvement is still poor. We investigated the role of the transcription factor nuclear factor (NF)-{kappa}B, which promotes cell survival in several other models, in the pathophysiology of Rb. The human Rb cell lines Y79 and WERI-Rb1 were treated with the cell permeable peptide SN50, that specifically inhibits the transcriptional activity of NF-{kappa}B by blocking its translocation into the nucleus. We found that NF-{kappa}B inhibition up-regulated Bax; down-regulated the anti-apoptotic proteins Bcl-2, A1, and cIAP-2; and induced loss of the mitochondrial transmembrane potential and caspase-independent, calpain-dependent apoptosis in Rb cells. Inhibition of the p38 kinase sensitized cells to SN50-induced cell death, whereas insulin-like growth factor-1 activated NF-{kappa}B and attenuated the proapoptotic effect of SN50. Finally, NF-{kappa}B inhibition sensitized Rb cells to doxorubicin. In conclusion, inhibition of NF-{kappa}B activity in Rb cells leads to loss of mitochondrial transmembrane potential and caspase-independent, calpain-dependent apoptosis. Therapeutic strategies targeting NF-{kappa}B could be beneficial in the clinical management of Rb, either alone or in combination with conventional chemotherapy.




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