Tumor-cell resistance to death receptor−induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax
Heidi LeBlanc1, 4, David Lawrence1, 4, Eugene Varfolomeev1, Klara Totpal1, John Morlan2, Peter Schow3, Sharon Fong1, Ralph Schwall1, Dominick Sinicropi2
& Avi Ashkenazi1
1
Department of Molecular Oncology, Genentech, South San Francisco, California, USA
2
Department of Analytical Assay Technology, Genentech, South San Francisco, California, USA
3
Department of Immunology, Genentech, South San Francisco, California, USA
4
H.L. and D.L contributed equally to this study.
Correspondence should be addressed to Avi Ashkenazi aa@gene.com
The importance of Bax for induction of tumor apoptosis through death receptors remains unclear. Here we show that Bax can be essential for death receptor−mediated apoptosis in cancer cells. Bax-deficient human colon carcinoma cells were resistant to death-receptor ligands, whereas Bax-expressing sister clones were sensitive. Bax was dispensable for apical death-receptor signaling events including caspase-8 activation, but crucial for mitochondrial changes and downstream caspase activation. Treatment of colon tumor cells deficient in DNA mismatch repair with the death-receptor ligand apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selected in vitro or in vivo for refractory subclones with Bax frameshift mutations including deletions at a novel site. Chemotherapeutic agents upregulated expression of the Apo2L/TRAIL receptor DR5 and the Bax homolog Bak in Bax-/- cells, and restored Apo2L/TRAIL sensitivity in vitro and in vivo. Thus, Bax mutation in mismatch repair−deficient tumors can cause resistance to death receptor−targeted therapy, but pre-exposure to chemotherapy rescues tumor sensitivity.
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated
