Antitumor effects of chloroquine/hydroxychloroquine mediated by inhibition of the NF-κB signaling pathway through abrogation of autophagic p47 degradation in adult T-cell leukemia/lymphoma cells.
Antitumor effects of chloroquine/hydroxychloroquine mediated by inhibition of the NF-κB signaling pathway through abrogation of autophagic p47 degradation in adult T-cell leukemia/lymphoma cells.
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DOI：
10.1371/journal.pone.0256320
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Morishita K
中科院分区：
文献类型：
--
作者：
Fauzi YR;Nakahata S;Chilmi S;Ichikawa T;Nueangphuet P;Yamaguchi R;Nakamura T;Shimoda K;Morishita K
成人T细胞白血病/淋巴瘤（ATLL）起源于人类T细胞白血病病毒1型（HTLV-1）感染，由于核因子-κB（NF-κB）信号通路的激活以维持增殖和生存。 ATLL 中 NF-κB 信号通路激活的一个重要机制是巨自噬（以下在本手稿的其余部分中称为自噬）的激活 - p47 (NSFL1C) 的溶酶体降解，p47 (NSFL1C) 是 NF-κB 通路的负调节因子。因此，我们考虑使用氯喹（CQ）或羟氯喹（HCQ）（CQ/HCQ）作为自噬抑制剂来治疗ATLL；这些药物最初被 FDA 批准作为抗疟药，最近被用于治疗自身免疫性疾病，例如系统性红斑狼疮 (SLE)。在本文中，我们确定了 CQ/HCQ 作为 NF-κB 抑制剂在通过阻断 p47 降解介导的 ATLL 中的治疗效果。对 ATLL 细胞系和原代 ATLL 细胞施用 CQ/HCQ 以剂量依赖性方式诱导细胞生长抑制，并且大多数细胞在 CQ 施用后发生凋亡。就分子机制而言，CQ处理的ATLL细胞中自噬受到抑制，并且随着p47水平的恢复，NF-κB通路的激活受到抑制。当使用移植 ATLL 细胞系的免疫缺陷小鼠检查 CQ/HCQ 的抗肿瘤作用时，CQ/HCQ 显着抑制肿瘤生长并提高 ATLL 异种移植小鼠模型的存活率。重要的是，在用于治疗 SLE 的剂量下，HCQ 在 ATLL 异种移植小鼠模型中选择性诱导 ATLL 细胞死亡。综上所述，我们的结果表明，CQ/HCQ 抑制自噬可能成为治疗 ATLL 的一种新颖且有效的策略。
Adult T-cell leukemia/lymphoma (ATLL) originates from human T-cell leukemia virus type 1 (HTLV-1) infection due to the activation of the nuclear factor-κB (NF-κB) signaling pathway to maintain proliferation and survival. An important mechanism of the activated NF-κB signaling pathway in ATLL is the activation of the macroautophagy (herafter referred to as autophagy in the remainder of this manuscript)-lysosomal degradation of p47 (NSFL1C), a negative regulator of the NF-κB pathway. Therefore, we considered the use of chloroquine (CQ) or hydroxychloroquine (HCQ) (CQ/HCQ) as an autophagy inhibitor to treat ATLL; these drugs were originally approved by the FDA as antimalarial drugs and have recently been used to treat autoimmune diseases, such as systemic lupus erythematosus (SLE). In this paper, we determined the therapeutic efficacy of CQ/HCQ, as NF-κB inhibitors, in ATLL mediated by blockade of p47 degradation. Administration of CQ/HCQ to ATLL cell lines and primary ATLL cells induced cell growth inhibition in a dose-dependent manner, and the majority of cells underwent apoptosis after CQ administration. As to the molecular mechanism, autophagy was inhibited in CQ-treated ATLL cells, and activation of the NF-κB pathway was suppressed with the restoration of the p47 level. When the antitumor effect of CQ/HCQ was examined using immunodeficient mice transplanted with ATLL cell lines, CQ/HCQ significantly suppressed tumor growth and improved the survival rate in the ATLL xenograft mouse model. Importantly, HCQ selectively induced ATLL cell death in the ATLL xenograft mouse model at the dose used to treat SLE. Taken together, our results suggest that the inhibition of autophagy by CQ/HCQ may become a novel and effective strategy for the treatment of ATLL.
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影响因子：
39.3
作者：
Liu T;Zhang L;Joo D;Sun SC
通讯作者：
Sun SC
影响因子：
5.4
作者：
Dewan, M. Zahidunnabi;Takamatsu, Naofumi;Morishita, Kazuhiro
通讯作者：
Morishita, Kazuhiro
DOI：
10.1073/pnas.77.12.7415
发表时间：
1980-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
POIESZ, BJ;RUSCETTI, FW;GALLO, RC
通讯作者：
GALLO, RC
影响因子：
--
作者：
Molejon, Maria Ines;Swayden, Mirna;Iovanna, Juan
通讯作者：
Iovanna, Juan
影响因子：
8
作者：
Matsuoka, M
通讯作者：
Matsuoka, M