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Autophagic degradation of NOXA underlies stromal cell-mediated resistance to proteasome inhibitors in mantle cell lymphoma
Leukemia Research ( IF 2.7 ) Pub Date : 2021-07-24 , DOI: 10.1016/j.leukres.2021.106672
Yoshiaki Kuroda 1 , Daisuke Koyama 2 , Jiro Kikuchi 2 , Shigehisa Mori 3 , Tatsuo Ichinohe 4 , Yusuke Furukawa 2
Affiliation  

Mantle cell lymphoma (MCL) is usually resistant to the current standard-of-care regimens and also to novel agents such as the proteasome inhibitor bortezomib. A better prognosis of leukemic variants of MCL suggests that MCL cells acquire drug resistance in nodal and/or bone marrow microenvironments via interaction with supporting cells. Bortezomib exerts cytotoxic action in MCL cells via stabilization of the pro-apoptotic BCL-2 family protein NOXA. Here we show that autophagic degradation of NOXA is a mechanism of bortezomib resistance in MCL cells in a tumor microenvironment. First, we demonstrated that interaction with bone marrow-derived or nodal stromal cells conferred bortezomib resistance to MCL cells in vitro and in a murine model. Co-culture of MCL cells with stromal cells enhanced bortezomib-induced ubiquitination and subsequent binding of NOXA to the p62 adaptor, which escorted NOXA to the lysosome for autophagic degradation. Finally, we found that not only direct contact with stromal cells but also stroma-derived humoral factors, especially interleukin-6, promoted selective autophagy and NOXA degradation in MCL cells. Targeting protective autophagy, for example, using the lysosome inhibitor chloroquine, might increase the efficacy of bortezomib-containing regimens in MCL.



中文翻译:

NOXA的自噬降解是基质细胞介导的套细胞淋巴瘤对蛋白酶体抑制剂耐药的基础

套细胞淋巴瘤 (MCL) 通常对当前的标准治疗方案以及蛋白酶体抑制剂硼替佐米等新药耐药。MCL 白血病变体的更好预后表明 MCL 细胞通过与支持细胞的相互作用在淋巴结和/或骨髓微环境中获得耐药性。Bortezomib通过稳定促凋亡 BCL-2 家族蛋白 NOXA在 MCL 细胞中发挥细胞毒作用。在这里,我们表明 NOXA 的自噬降解是肿瘤微环境中 MCL 细胞中硼替佐米耐药的机制。首先,我们证明了与骨髓来源或结节基质细胞的相互作用在体外赋予了对 MCL 细胞的硼替佐米耐药性在小鼠模型中。MCL 细胞与基质细胞的共培养增强了硼替佐米诱导的泛素化和随后 NOXA 与 p62 接头的结合,从而护送 NOXA 进入溶酶体进行自噬降解。最后,我们发现不仅与基质细胞直接接触,而且基质衍生的体液因子,尤其是白细胞介素 6,促进了 MCL 细胞的选择性自噬和 NOXA 降解。靶向保护性自噬,例如,使用溶酶体抑制剂氯喹,可能会增加含硼替佐米方案在 MCL 中的疗效。

更新日期:2021-07-29
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