Bortezomib reduces the tumorigenicity of multiple myeloma via downregulation of upregulated targets in clonogenic side population cells.
Bortezomib reduces the tumorigenicity of multiple myeloma via downregulation of upregulated targets in clonogenic side population cells.
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DOI：
10.1371/journal.pone.0056954
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Tagawa H
中科院分区：
文献类型：
--
作者：
Nara M;Teshima K;Watanabe A;Ito M;Iwamoto K;Kitabayashi A;Kume M;Hatano Y;Takahashi N;Iida S;Sawada K;Tagawa H
癌症（包括多发性骨髓瘤）中的侧群（SP）细胞表现出肿瘤起始特征。在本研究中，我们从人骨髓瘤细胞系和原发性肿瘤中分离出SP细胞，以检测SP细胞中特异性表达的潜在治疗靶点。我们发现来自骨髓瘤细胞系（RPMI 8226、AMO1、KMS-12-BM、KMS-11）的 SP 细胞表达 CD138，非 SP 细胞包括 CD138 阴性群体。将SP和非SP细胞连续移植到NOD/Shi-scid IL-2γnul小鼠中表明，克隆性骨髓瘤SP细胞具有高度致瘤性并具有自我更新的能力。基因表达分析显示，来自五种MM细胞系（RPMI 8226、AMO1、KMS-12-BM、KMS-11、JJN3）的SP细胞表达参与细胞周期和有丝分裂的基因（例如CCNB1、CDC25C、CDC2、BIRC5、CENPE、SKA1、AURKB、KIFs、TOP2A、ASPM）、多梳（例如， EZH2、EPC1) 和泛素蛋白酶体（例如 UBE2D3、UBE3C、PSMA5）比非 SP 细胞更强。此外，CCNB1、AURKB、EZH2 和 PSMA5 在 8 个原发性骨髓瘤样本的 SP 中也上调。在此基础上，我们将极光激酶抑制剂 (VX-680) 和蛋白酶体抑制剂 (硼替佐米) 与 RPMI 8226 和 AMO1 细胞一起使用，以确定这些药物是否可用于选择性靶向骨髓瘤 SP。我们发现这两种药物都降低了 SP 分数，尽管硼替佐米比 VX-680 更有效，因为它能够降低磷酸组蛋白 H3 (p-hist.H3) 和 EZH2 的水平； VX-680 仅减少 p-hist。 H3。这是第一份表明某些癌基因在骨髓瘤 SP 中特异性表达的报告，并且硼替佐米可有效下调其产物的表达。我们的方法可能有助于筛选新的药物，以针对多发性骨髓瘤中具有强大肿瘤启动潜力的细胞群。
Side population (SP) cells in cancers, including multiple myeloma, exhibit tumor-initiating characteristics. In the present study, we isolated SP cells from human myeloma cell lines and primary tumors to detect potential therapeutic targets specifically expressed in SP cells. We found that SP cells from myeloma cell lines (RPMI 8226, AMO1, KMS-12-BM, KMS-11) express CD138 and that non-SP cells include a CD138-negative population. Serial transplantation of SP and non-SP cells into NOD/Shi-scid IL-2γnul mice revealed that clonogenic myeloma SP cells are highly tumorigenic and possess a capacity for self-renewal. Gene expression analysis showed that SP cells from five MM cell lines (RPMI 8226, AMO1, KMS-12-BM, KMS-11, JJN3) express genes involved in the cell cycle and mitosis (e.g., CCNB1, CDC25C, CDC2, BIRC5, CENPE, SKA1, AURKB, KIFs, TOP2A, ASPM), polycomb (e.g., EZH2, EPC1) and ubiquitin-proteasome (e.g., UBE2D3, UBE3C, PSMA5) more strongly than do non-SP cells. Moreover, CCNB1, AURKB, EZH2 and PSMA5 were also upregulated in the SPs from eight primary myeloma samples. On that basis, we used an aurora kinase inhibitor (VX-680) and a proteasome inhibitor (bortezomib) with RPMI 8226 and AMO1 cells to determine whether these agents could be used to selectively target the myeloma SP. We found that both these drugs reduced the SP fraction, though bortezomib did so more effectively than VX-680 due to its ability to reduce levels of both phospho-histone H3 (p-hist. H3) and EZH2; VX-680 reduced only p-hist. H3. This is the first report to show that certain oncogenes are specifically expressed in the myeloma SP, and that bortezomib effectively downregulates expression of their products. Our approach may be useful for screening new agents with which to target a cell population possessing strong tumor initiating potential in multiple myeloma.
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影响因子：
10.5
作者：
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通讯作者：
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5.2
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45.3
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