Abstract
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 Baxminus sign/minus sign 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.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Animals
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Antineoplastic Agents, Phytogenic / pharmacology
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins
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BH3 Interacting Domain Death Agonist Protein
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Camptothecin / pharmacology
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Carrier Proteins / metabolism
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Caspase 8
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Caspase 9
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Caspases / metabolism
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Colonic Neoplasms / drug therapy
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Colonic Neoplasms / metabolism
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Enzyme Activation
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Etoposide / pharmacology
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Fas-Associated Death Domain Protein
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Female
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Flow Cytometry
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Humans
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Membrane Glycoproteins / metabolism*
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Membrane Glycoproteins / therapeutic use
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Mice
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Mice, Nude
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Mitochondria / metabolism
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Mutation
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases
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Proteins / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-bcl-2*
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Random Allocation
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Receptors, Tumor Necrosis Factor / metabolism*
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Signal Transduction / physiology*
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TNF-Related Apoptosis-Inducing Ligand
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Transplantation, Heterologous
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / metabolism*
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Tumor Necrosis Factor-alpha / therapeutic use
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bcl-2-Associated X Protein
Substances
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents, Phytogenic
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Apoptosis Regulatory Proteins
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BAX protein, human
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BH3 Interacting Domain Death Agonist Protein
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BID protein, human
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Bax protein, mouse
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Bid protein, mouse
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Carrier Proteins
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FADD protein, human
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Fadd protein, mouse
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Fas-Associated Death Domain Protein
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Membrane Glycoproteins
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Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Tumor Necrosis Factor
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tnfsf10 protein, mouse
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Tumor Necrosis Factor-alpha
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bcl-2-Associated X Protein
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Etoposide
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Parp1 protein, mouse
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases
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CASP8 protein, human
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CASP9 protein, human
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Casp8 protein, mouse
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Casp9 protein, mouse
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Caspase 8
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Caspase 9
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Caspases
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Camptothecin