WRN-targeted therapy using inhibitors NSC 19630 and NSC 617145 induce apoptosis in HTLV-1-transformed adult T-cell leukemia cells.
WRN-targeted therapy using inhibitors NSC 19630 and NSC 617145 induce apoptosis in HTLV-1-transformed adult T-cell leukemia cells.
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DOI：
10.1186/s13045-016-0352-4
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发表时间：
2016-11-09
影响因子：
28.5
通讯作者：
Nicot C
中科院分区：
文献类型：
--
作者：
Moles R;Bai XT;Chaib-Mezrag H;Nicot C
人类 T 细胞白血病病毒 1 型 (HTLV-1) 感染与成人 T 细胞白血病/淋巴瘤 (ATLL) 相关，ATLL 是一种淋巴增殖性恶性肿瘤，预后不佳，治疗选择有限。最近的证据表明，HTLV-1 转化细胞在 DNA 复制和 DNA 修复方面都存在缺陷，这表明这些细胞可能对小型解旋酶抑制剂的治疗特别敏感。由于 WRN 基因编码的“维尔纳综合征 ATP 依赖性解旋酶”在细胞增殖和 DNA 修复中发挥着重要作用，因此我们假设抑制 WRN 活性可以作为靶向 ATLL 细胞的新策略。我们的分析表明 WRN 解旋酶抑制剂在体外 HTLV-1 转化细胞和 ATL 衍生细胞系中诱导细胞凋亡作用。通过细胞周期分析、XTT 增殖测定、克隆形成测定、膜联蛋白 V 染色和线粒体跨膜电位测量证明了细胞增殖的抑制和细胞凋亡的诱导。靶向抑制 WRN 解旋酶可诱导 HTLV-1 转化的白血病细胞的细胞周期停滞和细胞凋亡。 NSC 19630（WRN 抑制剂）治疗可诱导 S 期细胞周期停滞、线粒体膜电位破坏以及抗凋亡因子 Bcl-2 表达减少。这些事件与 ATL 细胞中 caspase-3 依赖性细胞凋亡的激活有关。我们鉴定了一些 ATL 细胞 ATL-55T 和 LMY1，它们对 NSC 19630 不太敏感，但对另一种 WRN 抑制剂 NSC 617145 敏感。WRN 对于 ATL 细胞的生存至关重要。我们的研究表明，用小抑制剂靶向 WRN 解旋酶是靶向 HTLV-1 转化的 ATL 细胞的一种新的有前景的策略。
Human T-cell leukemia virus type 1 (HTLV-1) infection is associated with adult T-cell leukemia/lymphoma (ATLL), a lymphoproliferative malignancy with a dismal prognosis and limited therapeutic options. Recent evidence shows that HTLV-1-transformed cells present defects in both DNA replication and DNA repair, suggesting that these cells might be particularly sensitive to treatment with a small helicase inhibitor. Because the “Werner syndrome ATP-dependent helicase” encoded by the WRN gene plays important roles in both cellular proliferation and DNA repair, we hypothesized that inhibition of WRN activity could be used as a new strategy to target ATLL cells. Our analysis demonstrates an apoptotic effect induced by the WRN helicase inhibitor in HTLV-1-transformed cells in vitro and ATL-derived cell lines. Inhibition of cellular proliferation and induction of apoptosis were demonstrated with cell cycle analysis, XTT proliferation assay, clonogenic assay, annexin V staining, and measurement of mitochondrial transmembrane potential. Targeted inhibition of the WRN helicase induced cell cycle arrest and apoptosis in HTLV-1-transformed leukemia cells. Treatment with NSC 19630 (WRN inhibitor) induces S-phase cell cycle arrest, disruption of the mitochondrial membrane potential, and decreased expression of anti-apoptotic factor Bcl-2. These events were associated with activation of caspase-3-dependent apoptosis in ATL cells. We identified some ATL cells, ATL-55T and LMY1, less sensitive to NSC 19630 but sensitive to another WRN inhibitor, NSC 617145. WRN is essential for survival of ATL cells. Our studies suggest that targeting the WRN helicase with small inhibitors is a novel promising strategy to target HTLV-1-transformed ATL cells.