Apoptosis and radiosensitization of Hodgkin cells by proteasome inhibition

Purpose: Malignant cells from Hodgkin's disease have been reported to be de fective in regulation of NF-kappa B activity. Ionizing radiation is known t o activate NF-kappa B, and it has been suggested that this pathway may prot ect cells from apoptosis following exposure to radiation and other therapeu tic agents. Defective NF-kappa B regulation in Hodgkin cells could therefor e dictate the response of this disease to therapy, as well as be responsibl e for maintaining the malignant phenotype, The purpose of this study was to explore whether NF-kappa B activity could be modulated in Hodgkin cells an d whether it determines the response of these cells to treatment with ioniz ing radiation and/or desamethasone. Methods and Materials: Activation of NF-kappa B in cells is accomplished in large part by degradation of its inhibitor I kappa B through the 26s prote asome. HD-My-Z Hodgkin cells were treated with the proteasome inhibitor MG- 132 or transduced with a dominant negative super-repressor I kappa B alpha, Clonogenic survival, apoptosis, proteasome activity, and NF-kappa B bindin g activity were monitored in response to ionizing radiation and/or dexameth asone treatment. Results: HD-My-Z Hodgkin cells had modest NF-kappa B levels but, unlike oth er cell types, did not decrease their level of constitutively active NF-kap pa B in response to proteasome inhibition,vith MG-132. In contrast, transdu ction with a non-phosphorable I kappa B alpha construct abolished expressio n. MG-132 did, however, induce apoptosis in HD-My-Z cells and sensitized th em to ionizing radiation. Dexamethasone treatment had no effect on NF-kappa B activity or clonogenic survival of Hodgkin cells, but protected them fro m irradiation, Conclusion: We conclude that inhibition of 26s proteasome activity can indu ce apoptosis in HD-My-Z Hodgkin cells and radiosensitize them, in spite of the fact that their constitutively active NF-kappa B levels are unaltered, The proteasome may be a promising new therapeutic target for intervention i n this disease. In contrast, the use of glucocorticoids in conjunction with radiation treatment for this tumor may require re-evaluation. (C) 2000 Els evier Science Inc.