Expression of the death gene Bik/Nbk promotes sensitivity to drug-induced apoptosis in corticosteroid-resistant T-cell lymphoma and prevents tumor growth in severe combined immunodeficient mice

Members of the Bcl-2 gene family have been implicated in the regulation of cell death induced by cytostatic drugs. In some malignancies such as B-cell lymphoma, there is evidence that high expression of Bcl-2 is an independen t negative prognostic marker and the overexpression of Bcl-2 has been shown to confer resistance to cytotoxic drugs by preventing drug-induced apoptos is. This function of Bcl-2 can be antagonized by apoptosis-promoting member s of the Bcl-2 family. We previously showed that overexpression of Bar rest ores the chemosensitivity of Bax-deficient breast cancer cell lines. Theref ore, we investigated whether the death-promoting Bcl-2 homologue Bik/Nbk ca n enhance cytostatic drug-induced apoptosis. As a model, we used the T cell leukemia H9 (CD3(+) and CD4(+)CD8(-)), which is resistant to corticosteroi d-induced cell death and does not express endogenous Bik/Nbk. Sensitivity f or drug-induced apoptosis was increased 10- to 39-fold in cells transfected with the full-length coding sequence of Bik/Nbk. In addition, apoptosis in duced via CD95/Fas or heat shock was increased to a similar extent. These d ata show that Bik/Nbk, which, unlike Bar, carries only a BH3 but no BH1 or BH2 domain may be a target to enhance chemosensitivity. The complete suppre ssion of tumor growth in a severe combined immunodeficient mouse xenotransp lant model suggests that, in analogy to Bar, Bik/Nbk may function as a tumo r suppressor gene. (C) 1999 by The American Society of Hematology.