Abstract
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.
Highlights
Apoptosis induced by cellular stress is often mediated by the intrinsic mitochondria-initiated cell death pathway.[2]
We examined whether inhibition of p38 and Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinases decreased apoptosis sensitization when cells were treated with other classes of spindle poisons
Treatment with p38 and JNK inhibitors systematically decreased the percentage of apoptotic cells (Figure 6). These results suggest that Epstein Barr virus (EBV)-infected cells render tumor protein 53 (TP53)-mutated BL cells sensitive to apoptosis induction by all classes of spindle poisons tested, an effect likely to be caused by activation of p38 and JNK MAP kinases
Summary
Apoptosis induced by cellular stress is often mediated by the intrinsic mitochondria-initiated cell death pathway.[2] This pathway, regulated by the members of the Bcl[2] family, converges on Bax and Bak activation by BH3-only subgroup of Bl2-related proteins (such as Bim, Bmf, Bid, p53 upregulated modulator of apoptosis (PUMA) or Noxa). Received 09.12.13; revised 20.2.14; accepted 21.2.14; Edited by H-U Simon p38/JNK sensitizes TP53-mutated cells to apoptosis M Farhat et al and degradation of the anti-apoptotic protein Mcl[1] and prevent Bax and Bak polymerization at the mitochondria membrane.[5] Long-term mitotic arrest induces inhibition of Bcl[2], mediated by JNK phosphorylation.[6]. Synthesis of these antimitotic agents is complex and in addition they have numerous toxic side effects like peripheral neuropathy, neutropenia and diarrhea[11] and emergence of multidrug-resistant phenotypes can be observed.[12,13]
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