Inhibition of IκBα phosphorylation potentiates regulated cell death induced by azidothymidine in HTLV-1 infected cells
Open Access
- 18 February 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death Discovery
- Vol. 6 (1), 1-13
- https://doi.org/10.1038/s41420-020-0243-x
Abstract
Adult T cell leukemia/lymphoma (ATL) can be susceptible, at least transiently, to treatments with azidothymidine (AZT) plus IFN alpha and/or arsenic trioxide. However, the real role of AZT in this effect is still unclear. In fact, while reverse transcriptase (RT) inhibition could explain reduction of clonal expansion and of renewal of HTLV-1 infected cells during ATL progression, this effect alone seems insufficient to justify the evident and prompt decrease of the pro-viral load in treated patients. We have previously demonstrated that AZT is endowed with an intrinsic pro-apoptotic potential towards both peripheral blood mononuclear cells from healthy donors or some tumor cell lines, but this cytotoxic potential cannot be fully achieved unless I kappa B alpha phosphorylation is inhibited. Since the constitutive activation of NF-kappa B (NF-kappa B) appears a common biological basis of HTLV-1-infected cells, a pharmacological inhibition of I kappa B alpha phosphorylation seems a potential strategy for treating and preventing HTLV-1 related pathologies. In this study, we have demonstrated that a combination treatment with the I kappa B alpha phosphorylation inhibitor Bay 11-7085 and AZT induced increased levels of regulated cell death (RCD) by apoptosis compared to the single treatments in HTLV-1 infected cells of different origin. Importantly, levels of RCD were considerably higher in infected cells in comparison with the uninfected ones. Inhibition of NF-kappa B activation following the combined treatment was confirmed by analysis of both gel-shift and functional activity of the NF-kappa B complex proteins, p65/p52. Moreover, a transcriptional analysis revealed that the addition of Bay 11-7085 to AZT treatment in HTLV-1-infected cells modified their transcriptional profile, by inducing the upregulation of some pro-apoptotic genes together with the downregulation of some anti-apoptotic genes. Our data suggest that addition of adequate concentrations of I kappa B alpha phosphorylation inhibitor to therapeutic regimens including AZT could be a promising strategy in ATL.Funding Information
- Ministero dell'Istruzione, dell'Università e della Ricerca (2017M8R7N9_002)
This publication has 53 references indexed in Scilit:
- Interferon-α (IFN-α) suppresses HTLV-1 gene expression and cell cycling, while IFN-α combined with zidovudin induces p53 signaling and apoptosis in HTLV-1-infected cellsRetrovirology, 2013
- D(−)lentiginosine-induced apoptosis involves the intrinsic pathway and is p53-independentCell Death & Disease, 2012
- Epidemiological Aspects and World Distribution of HTLV-1 InfectionFrontiers in Microbiology, 2012
- Susceptibility of Primary HTLV-1 Isolates from Patients with HTLV-1-Associated Myelopathy to Reverse Transcriptase InhibitorsViruses, 2011
- The host genomic environment of the provirus determines the abundance of HTLV-1–infected T-cell clonesBlood, 2011
- BID, BIM, and PUMA Are Essential for Activation of the BAX- and BAK-Dependent Cell Death ProgramScience, 2010
- Inhibition of NF-κB activation sensitizes U937 cells to 3′-azido-3′-deoxythymidine induced apoptosisCell Death & Disease, 2010
- The Human T-Cell Leukemia Virus Type 1 Tax Oncoprotein Requires the Ubiquitin-Conjugating Enzyme Ubc13 for NF-κB ActivationJournal of Virology, 2007
- Retroviral oncoprotein Tax deregulates NF‐κB by activating Tak1 and mediating the physical association of Tak1–IKKEMBO Reports, 2007
- Expression of the NF‐κB targets BCL2 and BIRC5/Survivin characterizes small B‐cell and aggressive B‐cell lymphomas, respectivelyThe Journal of Pathology, 2005