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)-kappaB, 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-kappaB by blocking its translocation into the nucleus. We found that
NF-kappaB 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-kappaB and attenuated the proapoptotic effect of SN50. Finally,
NF-kappaB inhibition sensitized Rb cells to
doxorubicin. In conclusion, inhibition of
NF-kappaB activity in Rb cells leads to loss of mitochondrial transmembrane potential and
caspase-independent,
calpain-dependent apoptosis. Therapeutic strategies targeting
NF-kappaB could be beneficial in the clinical management of Rb, either alone or in combination with conventional
chemotherapy.