MARCKS inhibition cooperates with autophagy antagonists to potentiate the effect of standard therapy against drug-resistant multiple myeloma
MARCKS inhibition cooperates with autophagy antagonists to potentiate the effect of standard therapy against drug-resistant multiple myeloma
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MARCKS 抑制与自噬拮抗剂协同作用，增强标准疗法对抗耐药多发性骨髓瘤的效果
DOI：
10.1016/j.canlet.2020.03.020
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发表时间：
2020-06-28
期刊：
影响因子：
9.7
通讯作者：
Chang, Hong
中科院分区：
文献类型：
--
作者：
Zhang, Lun;Rastgoo, Nasrin;Chang, Hong
豆蔻酰化富丙氨酸C激酶底物（MARCKS）的过表达与多发性骨髓瘤（MM）的耐药性和进展有关。MARCKS诱导的基础和对MM的影响尚不清楚。在这里，我们发现microRNA-34 a（miR-34 a）调节MARCKS翻译，并在耐药MM细胞中低表达，导致MARCKS蛋白水平增加。miR-34 a的过表达降低了MARCKS的表达，并使耐药细胞对抗骨髓瘤药物敏感。MARCKS肽抑制剂（MPS）对耐药MM细胞发挥剂量依赖性细胞毒性作用，对正常造血细胞的细胞毒性最小。MPS与蛋白酶抑制剂硼替佐米协同作用，在体外和MM异种移植模型中有效杀死耐药MM细胞。虽然MARCKS抑制杀死MM细胞，但它也增强了MARCKS抑制后持续生长的促生存自噬途径。因此，用MARCKS拮抗剂硼替佐米和自噬抑制剂氯喹联合治疗显著减少了耐药MM细胞系以及原代MM细胞中的肿瘤生长。这项研究揭示了涉及miR-34 a-MARCKS自动调节环的耐药机制，并为克服多发性骨髓瘤耐药的潜在新治疗策略提供了框架。
Overexpression of Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) is implicated in drug resistance and progression of multiple myeloma (MM). The basis for MARCKS induction and impact on MM are not known. Here we show that microRNA-34a (miR-34a), regulates MARCKS translation and is under-expressed in drug-resistant MM cells, leading to increased MARCKS protein level. Over-expression of miR-34a reduces MARCKS expression and sensitizes resistant cells to anti-myeloma drugs. A MARCKS peptide inhibitor (MPS) exerts a dose dependent cytotoxic effect on drug-resistant MM cells with minimal cytotoxicity to normal hematopoietic cells. MPS synergizes with the proteasomal-inhibitor bortezomib to effectively kill drug-resistant MM cells both in vitro and in a xenograft model of MM. While MARCKS inhibition killed MM cells, it also enhanced a pro-survival autophagic pathway that sustained growth following MARCKS inhibition. In accordance, combined treatment with MARCKS antagonists, bortezomib and the autophagy inhibitor, chloroquine, significantly diminished tumor growth in drug-resistant MM cell lines as well as primary MM cells. This study uncovers a mechanism of drug resistance involving miR-34a-MARCKS autoregulatory loop and provides a framework for a potentially new therapeutic strategy to overcome drug resistance in multiple myeloma.