PMID: 11316563Apr 24, 2001Paper

Enhancement of radiosensitivity by proteasome inhibition: implications for a role of NF-kappaB

International Journal of Radiation Oncology, Biology, Physics
S M RussoJames Cusack

Abstract

NF-kappaB is activated by tumor necrosis factor, certain chemotherapeutic agents, and ionizing radiation, leading to inhibition of apoptosis. NF-kappaB activation is regulated by phosphorylation of IkappaB inhibitor molecules that are subsequently targeted for degradation by the ubiquitin-proteasome pathway. PS-341 is a specific and selective inhibitor of the proteasome that inhibits NF-kappaB activation and enhances cytotoxic effects of chemotherapy in vitro and in vivo. The objective of this study was to determine if proteasome inhibition leads to enhanced radiation sensitivity. Inhibition of NF-kappaB activation in colorectal cancer cells was performed by treatment of LOVO cells with PS-341 or infection with an adenovirus encoding IkappaB super-repressor, a selective NF-kappaB inhibitor. Cells were irradiated at 0, 2, 4, 6, 8, and 10 Gy with or without inhibition of NF-kappaB. NF-kappaB activation was determined by electrophoretic mobility gel shift assay, and apoptosis was evaluated using the TUNEL assay. Growth and clonogenic survival data were obtained to assess effects of treatment on radiosensitization. In vitro results were tested in vivo using a LOVO xenograft model. NF-kappaB activation was induced by radiation and i...Continue Reading

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