Arsenic/interferon-a triggered apoptosis in HTLV-I transformed cells is associated with proteasome mediated tax degradation and reversal of NF-κB activation

Abstract

HTLV-I associated Adult T cell leukemia /lymphoma (ATL) is a malignancy of mature activated T cells resistant to conventional chemotherapy. The viral transactivator oncoprotein Tax plays a critical role in HTLV-I-induced transformation and resistance to apoptosis, through the activation of the NF-KB pathway by inducing IicB-a and IicE'-β degradation. We have previously shown that the combination of arsenic trioxide (As) and interferon-ot (IFN) is highly effective to induce cell cycle arrest and apoptosis in HTLVI positive cells compared to HTLV-1 negative T cells. We have also demonstrated that cell death induction by As and IFN in HTLV-I transformed cells is only partially dépendant upon caspase activation and is not associated with modulation of bcl-2, bax or p 53 expression. In this study, we show that the combination of As and IFN induces the downregulation of Tax by the proteasome in both HTLV-I transformed cells and in T-cdls transiently transfected with Tax. This is associated with an upregulation of iKB-a, tofiβ and iKB-e through inhibition of their proteasomal degradation. Furthermore, As/EN treatment inhibits NF-KB reporter gene induction after Tax transfection and results in a sharp decrease in RelA DNA binding NF-KB complexes in HTLV-I transformed cells due to the cytoplasmic retention of RelA. Although Tax was previously shown to bind proteasome subunits to enhance lKB-a degradation, using kinetic studies we showed that As alone increases lKB-a level before the occurrence of Tax down-regulation. This sugge sts that As and As/IFN alters the proteasome function qualitatively to differentially enhance Tax degradation and inhibit lKB-a degradation. Such specific targeting of the viral oncoprotein by IFN/As treatment, reminiscent of As targeting of PML/RARa in acute promyelocytic leukemia, provides strong rational for combined IFN/As therapy in ATL patients. Indeed, preliminary results of a phase II clinical trial in relapsed/refractory ATL patients are encouraging suggesting the possibility of introducing As in the first line therapy of ATL.SCOPUS: ar.jinfo:eu-repo/semantics/publishe