Upregulation of Bcl-x and Bfl-1 as a potential mechanism of chemoresistance, which can be overcome by NF-kappa B inhibition

In A549 human lung adenocarcinoma cells, we found that TNF-alpha and severa l commonly used chemotherapeutic agents upregulated the expression of Bcl-x and/or Bfl-1/A1 through an NF-kappa B-dependent pathway. While parental A5 49 cells were resistant to the cytotoxic effects of both TNF-alpha and chem otherapy agents, NF-kappa B-blocked A549 cells were sensitized to both. Exp ression of either Bcl-x or Bfl-1/A1 in the NF-kappa B-deficient cells at ph ysiological levels provided differential protection against TNF-alpha and c hemotherapeutic treatment. These studies provide a potential mechanism for the phenomenon of chemotherapy-induced chemoresistance, and also reveal a p otential strategy by which chemoresistance can be overcome.