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

• Published in: Blood 1999-08, Vol.94 (3), p.1100-1107
• Main Authors: Daniel, Peter T., Pun, Kwok-Tao, Ritschel, Silke, Sturm, Isrid, Holler, Jutta, Dörken, Bernd, Brown, Robin
• Format: Article
• Language: English
• Subjects: Adrenal Cortex Hormones - pharmacology; Adrenal Cortex Hormones - therapeutic use; Animals; Antineoplastic agents; Apoptosis - drug effects; Apoptosis - genetics; Apoptosis Regulatory Proteins; Biological and medical sciences; Cell Division - genetics; Chemotherapy; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Genes, bcl-2; Humans; Lymphoma, T-Cell - drug therapy; Lymphoma, T-Cell - genetics; Lymphoma, T-Cell - pathology; Medical sciences; Membrane Proteins; Mice; Mice, SCID; Mitochondrial Proteins; Neoplasm Transplantation; Pharmacology. Drug treatments; Protein Biosynthesis; Proteins - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V94.3.1100.415a16_1100_1107

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 independent negative prognostic marker and the overexpression of Bcl-2 has been shown to confer resistance to cytotoxic drugs by preventing drug-induced apoptosis. This function of Bcl-2 can be antagonized by apoptosis-promoting members of the Bcl-2 family. We previously showed that overexpression of Bax restores the chemosensitivity of Bax-deficient breast cancer cell lines. Therefore, we investigated whether the death-promoting Bcl-2 homologue Bik/Nbk can enhance cytostatic drug-induced apoptosis. As a model, we used the T-cell leukemia H9 (CD3+ and CD4+CD8−), which is resistant to corticosteroid-induced cell death and does not express endogenous Bik/Nbk. Sensitivity for drug-induced apoptosis was increased 10- to 39-fold in cells transfected with the full-length coding sequence of Bik/Nbk. In addition, apoptosis induced via CD95/Fas or heat shock was increased to a similar extent. These data show that Bik/Nbk, which, unlike Bax, carries only a BH3 but no BH1 or BH2 domain may be a target to enhance chemosensitivity. The complete suppression of tumor growth in a severe combined immunodeficient mouse xenotransplant model suggests that, in analogy to Bax, Bik/Nbk may function as a tumor suppressor gene.