The regulation of bcr-abl in hypoxia is through the mTOR pathway
The regulation of bcr-abl in hypoxia is through the mTOR pathway
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DOI：
10.1080/10428194.2020.1849679
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发表时间：
2020-11-28
影响因子：
2.6
通讯作者：
Tonissen, Kathryn F.
中科院分区：
文献类型：
--
作者：
Clapper, Erin;Di Trapani, Giovanna;Tonissen, Kathryn F.
慢性粒细胞白血病 (CML) 通常以融合癌蛋白 bcr-abl 的形成为特征。因此，大多数 CML 治疗都是 bcr-abl 特异性酪氨酸激酶抑制剂 (TKI)。 CML 治疗中的 TKI 耐药性正在成为控制这种疾病的主要障碍。一种经过充分研究的耐药形式是缺氧诱导的耐药，这种现象在许多其他癌症中也观察到。本研究旨在确定 TKI 对缺氧培养的 CML 细胞的疗效。据观察，缺氧时 bcr-abl 翻译严重停止，导致 TKI 无效。我们发现缺氧时 bcr-abl 蛋白水平被抑制的机制是通过 mTOR 途径，特别是通过核糖体蛋白 S6 (RPS6)。这些信息对于改善 CML 治疗至关重要，因为它可用于确定如何最好地对抗 CML 中缺氧引起的耐药性，并随后确定新的治疗靶点。
Chronic myeloid leukemia (CML) is usually characterized by the formation of the fusion onco-protein bcr-abl. Therefore, the majority of CML treatments are bcr-abl specific tyrosine kinase inhibitors (TKIs). TKI resistance in CML treatment is becoming a major obstacle in managing this disease. One well-studied form of drug resistance is hypoxia-induced drug resistance, a phenomenon observed in many other cancers. This study aimed to determine the efficacy of TKIs in CML cells cultured in hypoxia. It was observed that bcr-abl translation was severely halted in hypoxia, rendering TKIs ineffective. We found that the mechanism by which bcr-abl protein levels were being suppressed in hypoxia was through the mTOR pathway, specifically via ribosomal protein S6 (RPS6). This information is vital to the improvement of CML treatments, as it can be used to determine how to best combat hypoxia-induced drug resistance in CML and subsequently to identify new targets for treatment.