Ovatodiolide targets chronic myeloid leukemia stem cells by epigenetically upregulating hsa-miR-155, suppressing the BCR-ABL fusion gene and dysregulating the PI3K/AKT/mTOR pathway
Ovatodiolide targets chronic myeloid leukemia stem cells by epigenetically upregulating hsa-miR-155, suppressing the BCR-ABL fusion gene and dysregulating the PI3K/AKT/mTOR pathway
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Ovatodiolide 通过表观遗传上调 hsa-miR-155、抑制 BCR-ABL 融合基因和失调 PI3K/AKT/mTOR 通路来靶向慢性粒细胞白血病干细胞
DOI：
10.18632/oncotarget.23231
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发表时间：
2018-01-09
期刊：
影响因子：
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通讯作者：
Tong，Xiang-Min
中科院分区：
文献类型：
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作者：
Tu，Yue-Xing;Wang，Shi-Bing;Tong，Xiang-Min
慢性髓性白血病（CML）是一种骨髓增殖性病理，起源于造血肿瘤干细胞（hCSCs）由于Bcl-Abl费城染色体转化。然而，针对这些hCSCs作为一种有效的抗cml策略的探索相对较少。卵磷脂（Ovatodiolide, Ova）是一种天然的二萜类化合物，具有广泛的抗癌活性。在这项研究中，我们使用流式细胞术、western blot、RT-PCR、基因组定位和肿瘤球形成实验研究了卵细胞对CD34+/CD38−、CD34+/CD38+和未分类的K562细胞系的抗hcscs潜力。我们证明，与未分类的K562和CD34+/CD38+相比，CD34+/CD38−细胞显著富集Oct4、Sox2、CD133、Bcr-Abl、p-CrkL和p-Stat5蛋白和/或mRNA。此外，我们发现单独使用卵细胞或通过增强伊马替尼的治疗潜力，降低CML细胞系的活力（剂量依赖性），与癌症的干细胞无关，并显著抑制CD34+细胞中的Bcr-Abl， p-CrkL， Stat5和MDR蛋白表达水平。机制研究显示，hsa-miR-155的显著上调，导致ova处理的K562 CD34+/CD38−细胞中PIK3CA表达失调的减少。此外，卵细胞单独或联合伊马替尼抑制CD34+/CD38−细胞的hCSC特性，导致其形成肿瘤球的能力丧失，细胞凋亡增强，Bax/Bcl-2比值升高，PI3K/AKT/mTOR信号通路失调。总之，这些结果证明了卵细胞在CML中PI3K/AKT/mTOR信号介导的抗hcsc作用，并提示卵细胞可能作为小分子PI3K/mTOR双抑制剂，从而将其潜在益处扩展到其他mTOR介导的病理。
Chronic myeloid leukemia (CML) is a myeloproliferative pathology, originating from the hematopoietic cancer stem cells (hCSCs) due to the Bcl-Abl Philadelphia chromosome transformation. However, targeting these hCSCs as an effective anti-CML strategy is relatively less explored. Ovatodiolide (Ova) is a natural diterpenoid isolate of Anisomeles indica with broad anticancer activity. In this study, we investigated the anti-hCSCs potential of Ova against CD34+/CD38−, CD34+/CD38+, and unsorted K562 cell lines using flow cytometry, western blot, RT-PCR, genomic mapping, and tumorsphere formation assays. We demonstrated that compared to unsorted K562 and CD34+/CD38+, CD34+/CD38− cells were significantly enriched with Oct4, Sox2, CD133, Bcr-Abl, p-CrkL and p-Stat5 protein and/or mRNA. Furthermore, we showed that Ova alone or by enhancing the therapeutic potential of Imatinib, reduced the viability of CML cell lines, dose-dependently, irrespective of the cancer stemness, as well as markedly inhibit the Bcr-Abl, p-CrkL, Stat5, and MDR protein expression levels in CD34+ cells. Mechanistic investigations revealed a significant up-regulation of hsa-miR-155, which resulted in the reduction of dysregulating the PIK3CA expression in Ova-treated K562 CD34+/CD38− cells. Additionally, Ova alone or in combination with Imatinib suppressed the hCSC traits of the CD34+/CD38− cells, resulting in loss of their ability to form tumorspheres, enhanced apoptosis, increase in the Bax/Bcl-2 ratio, and dysregulation of the PI3K/AKT/mTOR signaling pathway. Together, these results demonstrate the PI3K/AKT/mTOR signaling-mediated anti-hCSC effect of Ova in CML, as well as suggest a likely role for Ova as a small molecule PI3K/mTOR dual inhibitor, thus, extending its potential benefit to other mTOR-mediated pathologies.