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 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.
Max Delbrück Center for Molecular Medicine; the Department of Hematology, Oncology and Tumor Immunology, Charité-Campus Berlin-Buch, Humboldt University, Berlin-Buch, Germany. pdaniel@mdc-berlin.de
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Daniel
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Pun
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Ritschel
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Sturm
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Holler
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Dörken
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Brown
D000305:Adrenal Cortex Hormones / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D002455:Cell Division / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D019254:Genes, bcl-2; D006801:Humans; D016399:Lymphoma, T-Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins; D051379:Mice; D016513:Mice, SCID; D024101:Mitochondrial Proteins; D009368:Neoplasm Transplantation; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics*
D000305:Adrenal Cortex Hormones; D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011506:Proteins