Inhibition of IκBα phosphorylation potentiates regulated cell death induced by azidothymidine in HTLV-1 infected cells.,Cell Death Discovery

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Inhibition of IκBα phosphorylation potentiates regulated cell death induced by azidothymidine in HTLV-1 infected cells.
Cell Death Discovery ( IF 6.1 ) Pub Date : 2020-02-18 , DOI: 10.1038/s41420-020-0243-x
Claudia Matteucci ₁ , Francesca Marino-Merlo ₂ , Antonella Minutolo ₁ , Emanuela Balestrieri ₁ , Elena Valletta ₁ , Beatrice Macchi ₃ , Antonio Mastino _{4,

5} , Sandro Grelli ₁

Affiliation

Adult T cell leukemia/lymphoma (ATL) can be susceptible, at least transiently, to treatments with azidothymidine (AZT) plus IFNα 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 IκBα phosphorylation is inhibited. Since the constitutive activation of NF-kappa B (NF-κB) appears a common biological basis of HTLV-1-infected cells, a pharmacological inhibition of IκBα 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 IκBα 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-κB activation following the combined treatment was confirmed by analysis of both gel-shift and functional activity of the NF-κB 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 IκBα phosphorylation inhibitor to therapeutic regimens including AZT could be a promising strategy in ATL.

中文翻译：

IκBα 磷酸化的抑制可增强 HTLV-1 感染细胞中叠氮胸苷诱导的调节性细胞死亡。

成人 T 细胞白血病/淋巴瘤 (ATL) 可能对叠氮胸苷 (AZT) 加 IFNα 和/或三氧化二砷治疗敏感，至少是暂时敏感。然而，AZT 在这种作用中的真正作用仍不清楚。事实上，虽然逆转录酶 (RT) 抑制可以解释 ATL 进展期间克隆扩增的减少和 HTLV-1 感染细胞更新的减少，但仅这种作用似乎不足以证明接受治疗的患者中前病毒载量明显且迅速的减少是合理的。我们之前已经证明，AZT 对健康供体的外周血单核细胞或某些肿瘤细胞系具有内在的促凋亡潜力，但除非抑制 IκBα 磷酸化，否则无法完全实现这种细胞毒性潜力。由于 NF-κB (NF-κB) 的组成型激活似乎是 HTLV-1 感染细胞的常见生物学基础，因此对 IκBα 磷酸化的药理学抑制似乎是治疗和预防 HTLV-1 相关病理的潜在策略。在这项研究中，我们证明，与单一治疗不同来源的 HTLV-1 感染细胞相比，IκBα 磷酸化抑制剂 Bay 11-7085 和 AZT 联合治疗可诱导细胞凋亡导致的调节性细胞死亡 (RCD) 水平增加。重要的是，与未感染的细胞相比，感染细胞中的 RCD 水平要高得多。通过分析 NF-κB 复合蛋白 p65/p52 的凝胶位移和功能活性，证实了联合治疗后 NF-κB 激活受到抑制。此外，转录分析表明，在 HTLV-1 感染的细胞中添加 Bay 11-7085 到 AZT 处理中，通过诱导一些促凋亡基因的上调和一些抗凋亡基因的下调，改变了它们的转录谱。我们的数据表明，在包括 AZT 在内的治疗方案中添加足够浓度的 IκBα 磷酸化抑制剂可能是 ATL 的一种有前景的策略。

更新日期：2020-02-18

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