AHSA1 is a promising therapeutic target for cellular proliferation and proteasome inhibitor resistance in multiple myeloma.
AHSA1 is a promising therapeutic target for cellular proliferation and proteasome inhibitor resistance in multiple myeloma.
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AHSA1是治疗多发性骨髓瘤细胞增殖和蛋白酶体抑制药耐药的有效靶点。
DOI：
10.1186/s13046-021-02220-1
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发表时间：
2022-01-06
期刊：
影响因子：
--
通讯作者：
Yang Y
中科院分区：
文献类型：
--
作者：
Gu C;Wang Y;Zhang L;Qiao L;Sun S;Shao M;Tang X;Ding P;Tang C;Cao Y;Zhou Y;Guo M;Wei R;Li N;Xiao Y;Duan J;Yang Y
目前，多发性骨髓瘤（MM）仍是一种难以治愈的浆细胞恶性肿瘤，迫切需要新的治疗靶点和药物。蟾毒灵是一种毒性很强但有效的抗癌化合物。我们以蟾蜍灵为探针，利用蛋白质组芯片技术筛选其潜在靶点，其中AHSA 1是蟾蜍灵的唯一靶点。采用MTT法、western blot、流式细胞术、免疫组化染色和体内移植模型检测AHSA 1对细胞增殖和耐药性的影响。通过免疫共沉淀、质谱分析、定点突变和微量热泳实验验证了蟾蜍灵和KU-177在AHSA 1/HSP 90中的作用机制。与正常对照相比，MM样本中AHSA 1表达增加，这与MM复发和不良结局显著相关。此外，AHSA 1在体外和体内促进MM细胞增殖和蛋白酶体抑制剂（PI）抗性。机制探讨表明AHSA 1作为HSP 90 A的辅助分子伴侣激活CDK 6和PSMD 2，这两个因子分别是MM增殖和PI抵抗的关键调节因子。另外，我们还发现AHSA 1-K137是蟾蜍灵在AHSA 1上的特异性结合位点，该位点的突变降低了AHSA 1与HSP 90 A的相互作用，抑制了AHSA 1介导CDK 6和PSMD 2的功能。有趣的是，我们发现了KU-177，一种AHSA 1选择性抑制剂，并发现KU-177靶向与蟾蜍灵相同的位点。蟾蜍灵和KU-177治疗阻碍了原发性MM和复发性MM患者样本中流动MRD阳性细胞的增殖。此外，KU-177消除了由AHSA 1升高诱导的细胞增殖和PI抗性，并降低了CDK 6和PSMD 2的表达。我们证明，AHSA 1可能作为一个有前途的治疗靶点的细胞增殖和蛋白酶体抑制剂耐药的多发性骨髓瘤。在线版本包含补充材料，可通过10.1186/s13046-021-02220-1获取。
Currently, multiple myeloma (MM) is still an incurable plasma cell malignancy in urgent need of novel therapeutic targets and drugs. Bufalin was known as a highly toxic but effective anti-cancer compound. We used Bufalin as a probe to screen its potential targets by proteome microarray, in which AHSA1 was the unique target of Bufalin. The effects of AHSA1 on cellular proliferation and drug resistance were determined by MTT, western blot, flow cytometry, immunohistochemistry staining and xenograft model in vivo. The potential mechanisms of Bufalin and KU-177 in AHSA1/HSP90 were verified by co-immunoprecipitation, mass spectrometry, site mutation and microscale thermophoresis assay. AHSA1 expression was increased in MM samples compared to normal controls, which was significantly associated with MM relapse and poor outcomes. Furthermore, AHSA1 promoted MM cell proliferation and proteasome inhibitor (PI) resistance in vitro and in vivo. Mechanism exploration indicated that AHSA1 acted as a co-chaperone of HSP90A to activate CDK6 and PSMD2, which were key regulators of MM proliferation and PI resistance respectively. Additionally, we identified AHSA1-K137 as the specific binding site of Bufalin on AHSA1, mutation of which decreased the interaction of AHSA1 with HSP90A and suppressed the function of AHSA1 on mediating CDK6 and PSMD2. Intriguingly, we discovered KU-177, an AHSA1 selective inhibitor, and found KU-177 targeting the same site as Bufalin. Bufalin and KU-177 treatments hampered the proliferation of flow MRD-positive cells in both primary MM and recurrent MM patient samples. Moreover, KU-177 abrogated the cellular proliferation and PI resistance induced by elevated AHSA1, and decreased the expression of CDK6 and PSMD2. We demonstrate that AHSA1 may serve as a promising therapeutic target for cellular proliferation and proteasome inhibitor resistance in multiple myeloma. The online version contains supplementary material available at 10.1186/s13046-021-02220-1.
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影响因子：
254.7
作者：
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通讯作者：
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