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.
机构:
Ares Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, SwitzerlandAres Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, Switzerland
Eskes, R
Desagher, S
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机构:
Ares Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, SwitzerlandAres Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, Switzerland
Desagher, S
Antonsson, B
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机构:
Ares Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, SwitzerlandAres Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, Switzerland
Antonsson, B
Martinou, JC
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机构:
Ares Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, SwitzerlandAres Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, Switzerland
机构:
Ares Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, SwitzerlandAres Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, Switzerland
Eskes, R
Desagher, S
论文数: 0引用数: 0
h-index: 0
机构:
Ares Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, SwitzerlandAres Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, Switzerland
Desagher, S
Antonsson, B
论文数: 0引用数: 0
h-index: 0
机构:
Ares Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, SwitzerlandAres Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, Switzerland
Antonsson, B
Martinou, JC
论文数: 0引用数: 0
h-index: 0
机构:
Ares Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, SwitzerlandAres Serono Int SA, Serono Pharmaceut Res Inst, CH-1228 Geneva, Switzerland