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Blood, Vol. 94 No. 3 (August 1), 1999:
pp. 1100-1107
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
Peter T. Daniel,
Kwok-Tao Pun,
Silke Ritschel,
Isrid Sturm,
Jutta Holler,
Bernd Dörken, and
Robin Brown
From the Max Delbrück Center for Molecular Medicine; the
Department of Hematology, Oncology and Tumor Immunology,
Charité Campus Berlin-Buch, Humboldt University, Berlin-Buch,
Germany; and the Cell Biology Unit, Glaxo Wellcome Medicines Research
Centre, Stevenage, United Kingdom.
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.
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