聚（ADP-核糖）聚合酶1（PARP1）通过下调微小RNA-192-5p-AKT信号通路促进来那度胺耐药多发性骨髓瘤的肿瘤增殖。
PARP1 promotes tumor proliferation in lenalidomide-resistant multiple myeloma via the downregulation of microRNA-192-5p-AKT signaling.
作者信息
Luo Yuqing, Chen Yalu, Ai Cheng, Huang Xiaguang, Perna Fabiana, Kale Brandon J, Lim Say Min, Gu Meier, Gao Panpan, Rong Chunmeng, Zhou Zefeng, Weng Yiqin, Jiang Yinyan, Yang Fang, Xia Yongming
机构信息
Department of Hematology, Yuyao People's Hospital of Zhejiang Province, The Affiliated Yangming Hospital of Ningbo University, Yuyao, China.
Department of Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
出版信息
Transl Cancer Res. 2024 Nov 30;13(11):6273-6281. doi: 10.21037/tcr-24-1543. Epub 2024 Nov 21.
BACKGROUND
Lenalidomide-based therapies are recommended as first-line treatment for multiple myeloma (MM) patients, regardless of the transplant eligibility. Resistance to lenalidomide is a clinical problem that urgently needs to be addressed. The expression of poly(ADP-ribose) polymerase 1 (PARP1) is abnormally high in a variety of tumor tissues including MM. However, in lenalidomide-resistant MM, it is not yet known whether the abnormally high expression of PARP1 is involved in the occurrence of drug resistance, and whether the inhibition of PARP1 can reverse lenalidomide resistance. The aim of this study was to investigate the mechanism of PARP1 promoting lenalidomide-resistant in MM patients.
METHODS
Samples of bone marrow from patients with MM who were sensitive or resistant to lenalidomide were collected. The expression levels of PARP1 at the messenger RNA and protein levels were detected through polymerase chain reaction and western blot. MM cell lines were cultivated , cell lines resistant to lenalidomide were screened out, and the expression levels of PARP1 in the resistant cell lines were detected. The apoptosis level was also detected in the lenalidomide-resistant MM cell lines treated with a PARP1 inhibitor. The proliferation rates of the two groups of cells at different time points were evaluated by mono-methyl terephthalate (MMT) experiments. Finally, the effect of PARP1 on the proliferation of lenalidomide-resistant MM through the microRNA-192-5p-AKT signaling pathway was analyzed.
RESULTS
In the lenalidomide-resistant cell lines, the expression level of PARP1 was higher, the proliferation more rapid, and the apoptosis rate was lower than lenalidomide-sensitive cell lines. Additionally, the activated AKT pathway was suppressed by downregulating the expression of microRNA-192-5p. MM resistance can be inhibited to some extent by impacting PARP1.
CONCLUSIONS
PARP1 is involved in the production of lenalidomide resistance in MM, and could serve as a potential target for the treatment of MM in the future.
背景
基于来那度胺的疗法被推荐作为多发性骨髓瘤（MM）患者的一线治疗方案，无论其是否适合移植。来那度胺耐药是一个亟待解决的临床问题。聚（ADP - 核糖）聚合酶1（PARP1）在包括MM在内的多种肿瘤组织中表达异常增高。然而，在来那度胺耐药的MM中，PARP1的异常高表达是否参与耐药的发生，以及抑制PARP1是否能逆转来那度胺耐药尚不清楚。本研究旨在探讨PARP1促进MM患者来那度胺耐药的机制。
方法
收集对来那度胺敏感或耐药的MM患者的骨髓样本。通过聚合酶链反应和蛋白质免疫印迹法检测PARP1在信使核糖核酸和蛋白质水平的表达。培养MM细胞系，筛选出来那度胺耐药细胞系，并检测耐药细胞系中PARP1的表达水平。还用PARP1抑制剂处理来那度胺耐药的MM细胞系，检测其凋亡水平。通过3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐（MTT）实验评估两组细胞在不同时间点的增殖率。最后，分析PARP1通过微小核糖核酸-192-5p-AKT信号通路对来那度胺耐药MM增殖的影响。
结果
在来那度胺耐药细胞系中，PARP1的表达水平更高，增殖更快，凋亡率低于来那度胺敏感细胞系。此外，下调微小核糖核酸-192-5p的表达可抑制激活的AKT通路。影响PARP1可在一定程度上抑制MM耐药。
结论
PARP1参与MM中来那度胺耐药的产生，未来可能成为MM治疗的潜在靶点。
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