Disulfiram/copper targets stem cell-like ALDH+ population of multiple myeloma by inhibition of ALDH1A1 and Hedgehog pathway
Disulfiram/copper targets stem cell-like ALDH+ population of multiple myeloma by inhibition of ALDH1A1 and Hedgehog pathway
复制标题
双硫仑/铜通过抑制 ALDH1A1 和 Hedgehog 通路靶向多发性骨髓瘤干细胞样 ALDH() 群体
DOI：
10.1002/jcb.26885
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发表时间：
2018-08-01
影响因子：
4
通讯作者：
Zhang, Liling
中科院分区：
文献类型：
--
作者：
Jin, Na;Zhu, Xiaojian;Zhang, Liling
多发性骨髓瘤干细胞（MMSC）被认为是导致复发的主要原因。根除 MMSC 可能是改善多发性骨髓瘤 (MM) 预后的有效策略。已发现 MMSC 中乙醛脱氢酶 (ALDH) 活性增加，但抑制 ALDH 活性是否可以消除 MMSC 仍不清楚。据报道，双硫仑 (DS) 是 ALDH 的抑制剂，并且越来越多的研究表明它以铜 (Cu) 依赖性方式具有抗癌作用。在本研究中，我们通过Aldeflor检测分离了MM的ALDH(+)细胞，并证明它们具有体外和体内的致瘤能力。接下来，我们在体外和体内研究了含或不含 Cu 的 DS 对抑制 MM 干性的影响。我们发现 DS/Cu 消除了类干细胞 ALDH(+) 细胞。此外，我们证明 DS/Cu 抑制干细胞转录因子 NANOG 和 OCT4 的表达，并消除 MM 的克隆形成性。我们还表明，DS/Cu 可减少异种移植模型中的肿瘤生长并抑制 MM 的干性。我们进一步发现DS/Cu的特异性靶点是ALDH1A1，并且DS/Cu至少部分抑制了ALDH1A1调控的Hedgehog（Hh）通路转录因子Gli1和Gli2。我们的数据表明，DS/Cu 可以通过 ALDH1A1 和 Hh 途径抑制 ALDH(+) 干细胞样细胞，这可能是根除 MM 干细胞样细胞的有前途的治疗剂。
Multiple myeloma stem cells (MMSCs) have been considered as the major cause resulting in relapse. Eradicating MMSCs may be an effective strategy to improve the outcome of multiple myeloma (MM). Increased activity of aldehyde dehydrogenase (ALDH) has been found in MMSCs, but whether inhibiting ALDH activity can eliminate MMSCs remains unknown. Disulfiram (DS) has been reported as an inhibitor of ALDH, and increasing studies showed it has anti-cancer effects in a copper (Cu)-dependent manner. In this study, we isolated ALDH(+) cells of MM by Aldefluor assay and demonstrated they possessed tumorigenesis capacities in vitro and in vivo. Next, we investigated the effects of DS with or without Cu on suppressing the stemness of MM both in vitro and in vivo. We found that DS/Cu eliminated the stem cell-like ALDH(+) cells. Furthermore, we demonstrated that DS/Cu inhibited the expression of stem cell transcription factors NANOG and OCT4, and abolished the clonogenicity of MM. We also showed that DS/Cu reduced the tumor growth and inhibited stemness of MM in xenograft model. We further found the specific target of DS/Cu is ALDH1A1 and DS/Cu inhibited the Hedgehog (Hh) pathway transcription factors Gli1 and Gli2 regulated by ALDH1A1 at least in part. Our data suggest that DS/Cu can inhibit the ALDH(+) stem cell-like cells through ALDH1A1 and Hh pathway, which may be a promising therapeutic agent in eradicating stem cell-like cells of MM.