Pang Jianan, Shi Qiaofa, Liu Zhiqiang, He Jin, Liu Huan, Lin Pei, Cui Jiuwei, Yang Jing
Cancer Center, The First Hospital of Jilin University, Changchun, Jilin Province, China.
Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Haematologica. 2017 Jul;102(7):1273-1280. doi: 10.3324/haematol.2016.154062. Epub 2017 Mar 30.
Despite advances in therapy, multiple myeloma remains incurable, with a high frequency of relapse. This suggests the need to identify additional factors that contribute to drug resistance. Our previous studies revealed that bone marrow adipocytes promote resistance to chemotherapy in myeloma through adipocyte-secreted adipokines, but the mechanism underlying this effect and the specific adipokines involved are not well understood. We proposed to determine the role of resistin, an adipokine that is secreted by adipocytes, in chemotherapy resistance in myeloma. We found that resistin abrogated chemotherapy-induced apoptosis in established myeloma cell lines and primary myeloma samples. Resistin inhibited chemotherapy-induced caspase cleavage through the NF-κB and PI3K/Akt pathways. Resistin also increased the expression and drug efflux function of ATP-binding cassette (ABC) transporters in myeloma cells through decreasing the expression of both DNA methyltransferases DNMT1 and DNMT3a and the methylation levels of gene promoters. studies further demonstrated the protective effect of resistin in chemotherapy-induced apoptosis. Our study thus reveals a new biological function of resistin in the pathogenesis of myeloma, with the implication that targeting resistin could be a potential strategy to prevent or overcome multidrug resistance in myeloma.
尽管治疗方法有所进步，但多发性骨髓瘤仍然无法治愈，复发频率很高。这表明需要识别出更多导致耐药性的因素。我们之前的研究表明，骨髓脂肪细胞通过脂肪细胞分泌的脂肪因子促进骨髓瘤对化疗的耐药性，但这种效应的潜在机制以及所涉及的具体脂肪因子尚不清楚。我们建议确定抵抗素（一种由脂肪细胞分泌的脂肪因子）在骨髓瘤化疗耐药中的作用。我们发现，抵抗素消除了在已建立的骨髓瘤细胞系和原发性骨髓瘤样本中化疗诱导的细胞凋亡。抵抗素通过NF-κB和PI3K/Akt途径抑制化疗诱导的半胱天冬酶裂解。抵抗素还通过降低DNA甲基转移酶DNMT1和DNMT3a的表达以及基因启动子的甲基化水平，增加了骨髓瘤细胞中ATP结合盒（ABC）转运蛋白的表达和药物外排功能。研究进一步证明了抵抗素对化疗诱导的细胞凋亡的保护作用。因此，我们的研究揭示了抵抗素在骨髓瘤发病机制中的一种新的生物学功能，这意味着靶向抵抗素可能是预防或克服骨髓瘤多药耐药的一种潜在策略。
