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Apoptosis and radiosensitization of hodgkin cells by proteasome inhibition
F Pajonk1, K Pajonk, W H McBride
1Department of Radiation Oncology, Experimental Division, Roy E. Coats Research Laboratories, UCLA School of Medicine, Los Angeles, CA 90095-1714, USA.
Purpose:
Malignant cells from Hodgkin's disease have been reported to be defective in regulation of NF-kappaB activity. Ionizing radiation is known to activate NF-kappaB, and it has been suggested that this pathway may protect cells from apoptosis following exposure to radiation and other therapeutic agents. Defective NF-kappaB regulation in Hodgkin cells could therefore dictate the response of this disease to therapy, as well as be responsible for maintaining the malignant phenotype. The purpose of this study was to explore whether NF-kappaB activity could be modulated in Hodgkin cells and whether it determines the response of these cells to treatment with ionizing radiation and/or dexamethasone.
Methods And Materials:
Activation of NF-kappaB in cells is accomplished in large part by degradation of its inhibitor IkappaB through the 26s proteasome. HD-My-Z Hodgkin cells were treated with the proteasome inhibitor MG-132 or transduced with a dominant negative super-repressor IkappaBalpha. Clonogenic survival, apoptosis, proteasome activity, and NF-kappaB binding activity were monitored in response to ionizing radiation and/or dexamethasone treatment.
Results:
HD-My-Z Hodgkin cells had modest NF-kappaB levels but, unlike other cell types, did not decrease their level of constitutively active NF-kappaB in response to proteasome inhibition with MG-132. In contrast, transduction with a non-phosphorable IkappaBalpha construct abolished expression. MG-132 did, however, induce apoptosis in HD-My-Z cells and sensitized them to ionizing radiation. Dexamethasone treatment had no effect on NF-kappaB activity or clonogenic survival of Hodgkin cells, but protected them from irradiation.
Conclusion:
We conclude that inhibition of 26s proteasome activity can induce apoptosis in HD-My-Z Hodgkin cells and radiosensitize them, in spite of the fact that their constitutively active NF-kappaB levels are unaltered. The proteasome may be a promising new therapeutic target for intervention in this disease. In contrast, the use of glucocorticoids in conjunction with radiation treatment for this tumor may require re-evaluation.