期刊
JOURNAL OF IMMUNOLOGY
卷 175, 期 4, 页码 2174-2183出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.175.4.2174
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- FIC NIH HHS [D43TW00013] Funding Source: Medline
- NIAID NIH HHS [AI28697] Funding Source: Medline
Rituximab treatment of B non-Hodgkin's lymphoma (NHL) cell lines inhibits the constitutive NF-kappa B activity and results in the sensitization of tumor cells to both chemotherapy and Fas-induced apoptosis. Cells expressing dominant active I kappa B or treated with NF-kappa B-specific inhibitors were sensitive to both drugs and Fas agonist mAb (CH-11)-induced apoptosis. Down-regulation of Bel-x(L) expression via inhibition of NF-kappa B activity correlated with chemosensitivity. The direct role of Bcl-x(L) in chemoresistance was demonstrated by the use of Bcl-x(L)-overexpressing Ramos cells, Ramos hemagglutinin (HA)-Bcl-x, which were not sensitized by rituximab to drug-induced apoptosis. However, inhibition of Bcl-x(L) in Ramos HA-Bcl-x resulted in sensitization to drug-induced apoptosis. The role of Bcl-x(L) expression in the regulation of Fas resistance was not apparent; Ramos HA-Bcl-x cells were as sensitive as the wild type to CH-11-induced apoptosis. Several lines of evidence support the direct role of the transcription repressor yin-yang I (YY1) in the regulation of resistance to CH-11-induced apoptosis. Inhibition of YY1 activity by either rituximab or the NO donor DETANONOate or after transfection with YY1 small interfering RNA resulted in up-regulation of Fas expression and sensitization to CH-11-induced apoptosis. These findings suggest two mechanisms underlying the chemosensitization and immunosensitization of B-NHL cells by rituximab via inhibition of NF-kappa B. The regulation of chemoresistance by NF-kappa B is mediated via Bcl-xL expression, whereas the regulation of Fas resistance by NF-kappa B is mediated via YY1 expression and activity. The potential clinical significance of these findings is discussed.
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