3-Methyladenine but not antioxidants to overcome BACH2-mediated bortezomib resistance in mantle cell lymphoma.
3-Methyladenine but not antioxidants to overcome BACH2-mediated bortezomib resistance in mantle cell lymphoma.
复制标题
3-甲基腺嘌呤而非抗氧化剂可克服套细胞淋巴瘤中 BACH2 介导的硼替佐米耐药性
DOI：
10.1186/s12935-021-01980-2
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发表时间：
2021-05-26
影响因子：
5.8
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Feng M;Wang J;Sun M;Li G;Li B;Zhang H
硼替佐米 (BTZ) 是一种蛋白酶体抑制剂，已用于治疗套细胞淋巴瘤 (MCL) 患者，但临床病例对 BTZ 的耐药性仍然是一个主要缺点。 BACH2 是一种淋巴特异性转录抑制因子，被认为是 MCL 中的肿瘤抑制因子。 BACH2 水平降低有助于 BTZ 耐药；然而，BACH2 介导的 BTZ 耐药性背后的分子事件在很大程度上尚不清楚。我们使用慢病毒shRNA介导的敲低系统沉默了MCL细胞中的BACH2。通过生物信息学、实时 RT-PCR、免疫印迹和一系列功能分析来描述 MCL 中 BTZ 耐药的分子机制。在耐药性 MCL 细胞系和异种移植物中的许多细胞和分子过程中评估了化学物质的治疗效果。在耐药细胞中，BTZ 触发的轻度氧化应激诱导 PI3K-AKT 信号的强烈激活，从而进一步阻止 BACH2 的核转位。 BACH2 的缺陷核易位或沉默 BACH2 消除了其对 HMOX1 的转录抑制，导致血红素加氧酶-1 (HO-1) 上调。 HO-1 的增加进一步将活性氧 (ROS) 维持在最低的促肿瘤水平，并增强了细胞保护性自噬。有趣的是，虽然ROS的轻微增加对耐药细胞表现出促肿瘤作用，但简单地用抗氧化剂阻断ROS并不会导致细胞死亡，而是通过稳定BACH家族的另一个成员BACH1而加剧BTZ耐药性。相反，3-甲基腺嘌呤 (3-MA)（一种抑制 PI3K 信号传导和自噬体形成的双重抑制剂）在体外和体内均可使耐药 MCL 细胞对 BTZ 敏感。我们的结果剖析了耐药 MCL 细胞中相互关联的分子网络，其中 3-MA 代表了克服 BTZ 耐药性的有效治疗策略。值得注意的是，BACH1 和 BACH2 尽管来自同一家族，但可能在 MCL 的发病机制和进展中发挥相反的作用。
Bortezomib (BTZ) is an inhibitor of the proteasome that has been used to treat patients with mantle cell lymphoma (MCL), but the resistance to BTZ in clinical cases remains a major drawback. BACH2 is a lymphoid-specific transcription repressor recognized as a tumor suppressor in MCL. Reduced BACH2 levels contribute to BTZ resistance; however, the molecular events underlying BACH2-mediated BTZ resistance are largely unclear. We silenced BACH2 in MCL cells using a lentiviral shRNA-mediated knockdown system. Bioinformatic, real-time RT-PCR, immunoblotting and a series of functional assays were performed to describe the molecular mechanisms underlying BTZ resistance in MCL. The therapeutic effects of chemicals were evaluated on numerous cellular and molecular processes in resistant MCL cell lines and xenografts. In resistant cells, BTZ-triggered mild oxidative stress induced a strong activation of PI3K-AKT signaling, which further blocked nuclear translocation of BACH2. Defective nuclear translocation of BACH2 or silencing BACH2 removed its transcriptional repression on HMOX1, leading to upregulation of heme oxygenase-1 (HO-1). Increased HO-1 further maintained reactive oxygen species (ROS) within a minimal tumor-promoting level and enhanced cytoprotective autophagy. Interestingly, although mild increase in ROS exhibited a pro-tumorigenic effect on resistant cells, simply blocking ROS by antioxidants did not lead to cell death but aggravated BTZ resistance via stabilizing BACH1, the other member of BACH family. Instead, 3-methyladenine (3-MA), a dual inhibitor to suppress PI3K signaling and autophagosome formation, sensitized resistant MCL cells to BTZ, both in vitro and in vivo. Our results dissected the interconnected molecular network in resistant MCL cells in which 3-MA represents an effective therapeutic strategy to overcome BTZ resistance. Notably, BACH1 and BACH2, albeit from the same family, are likely to play opposite roles in pathogenesis and progression of MCL.
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