Reversion of apoptotic resistance of TP53-mutated Burkitt lymphoma B-cells to spindle poisons by exogenous activation of JNK and p38 MAP kinases.
Defects in apoptosis are frequently the cause of cancer emergence, as well as cellular resistance to chemotherapy. These phenotypes may be due to mutations of the tumor suppressor TP53 gene. In this study, we examined the effect of various mitotic spindle poisons, including the new isocombretastatin derivative isoNH2CA-4 (a tubulin-destabilizing molecule, considered to bind to the colchicine site by analogy with combretastatin A-4), on BL (Burkitt lymphoma) cells. We found that resistance to spindle poison-induced apoptosis could be reverted in tumor protein p53 (TP53)-mutated cells by EBV (Epstein Barr virus) infection. This reversion was due to restoration of the intrinsic apoptotic pathway, as assessed by relocation of the pro-apoptotic molecule Bax to mitochondria, loss of mitochondrial integrity and activation of the caspase cascade with PARP (poly ADP ribose polymerase) cleavage. EBV sensitized TP53-mutated BL cells to all spindle poisons tested, including vincristine and taxol, an effect that was systematically downmodulated by pretreatment of cells with inhibitors of p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases. Exogenous activation of p38 and JNK pathways by dihydrosphingosine reverted resistance of TP53-mutated BL cells to spindle poisons. Dihydrosphingosine treatment of TP53-deficient Jurkat and K562 cell lines was also able to induce cell death. We conclude that activation of p38 and JNK pathways may revert resistance of TP53-mutated cells to spindle poisons. This opens new perspectives for developing alternative therapeutic strategies when the TP53 gene is inactivated.
Univ Limoges, Faculté de Médecine, CNRS UMR 7276, Laboratoire CRIBL, Limoges, France.
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Farhat
Univ Limoges, Faculté de Médecine, CNRS UMR 7276, Laboratoire CRIBL, Limoges, France.
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Poissonnier
Univ Paris Sud, Faculté de Pharmacie, CNRS UMR 8076, Laboratoire BioCIS, Châtenay Malabry, France.
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Hamze
Univ Limoges, Faculté de Médecine, CNRS UMR 7276, Laboratoire CRIBL, Limoges, France.
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Ouk-Martin
Univ Paris Sud, Faculté de Pharmacie, CNRS UMR 8076, Laboratoire BioCIS, Châtenay Malabry, France.
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Brion
Univ Paris Sud, Faculté de Pharmacie, CNRS UMR 8076, Laboratoire BioCIS, Châtenay Malabry, France.
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Alami
1] Univ Limoges, Faculté de Médecine, CNRS UMR 7276, Laboratoire CRIBL, Limoges, France [2] CHU Limoges, Hôpital Dupuytren, Service d'hématologie, Limoges, France.
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Feuillard
Univ Limoges, Faculté de Médecine, CNRS UMR 7276, Laboratoire CRIBL, Limoges, France.
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Jayat-Vignoles
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology*; D002051:Burkitt Lymphoma / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D020128:Inhibitory Concentration 50; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D008941:Spindle Apparatus / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D047428:Protein Kinase Inhibitors; D016159:Tumor Suppressor Protein p53; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013110:Sphingosine; C005682:safingol