Metformin suppresses the growth of leukemia cells partly through downregulation of AXL receptor tyrosine kinase
Metformin suppresses the growth of leukemia cells partly through downregulation of AXL receptor tyrosine kinase
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DOI：
10.1016/j.leukres.2020.106383
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发表时间：
2020-07-01
影响因子：
2.7
通讯作者：
Tohda, Shuji
中科院分区：
文献类型：
--
作者：
Saito, Tatsuya;Itoh, Mai;Tohda, Shuji
二甲双胍是一种抗糖尿病药物，已知通过抑制雷帕霉素（mTOR）的机制靶点而具有抗癌活性；然而，也可能涉及其他分子机制。在这项研究中，我们研究了二甲双胍对 TAM（TYRO3、AXL 和 MERTK）家族受体酪氨酸激酶活性的影响，这些受体在白血病细胞生长中发挥着重要作用。结果表明，二甲双胍以剂量依赖性方式抑制四种白血病细胞系OCI/AML2、OCI/AML3、THP-1和K562的体外生长，这与下调AXL的表达和磷酸化以及抑制其下游靶标例如STAT3的磷酸化相对应。此外，二甲双胍增强了小分子 AXL 抑制剂 TP-0903 对 OCI/AML3 和 K562 细胞生长的抑制作用，并阻止 K562 细胞中阿霉素诱导的 AXL 激活，从而诱导白血病细胞产生化疗耐药性，从而增强阿霉素的抗增殖作用。鉴于二甲双胍还下调 TYRO3 的表达和 MERTK 的磷酸化，这些发现表明二甲双胍发挥的抗白血病作用可能部分归因于 TAM 激酶的抑制。因此，二甲双胍对于 AXL 和其他 TAM 蛋白以及激活的 mTOR 白血病细胞呈阳性的患者具有临床潜力。
Metformin is an anti-diabetic drug known to have anticancer activity by inhibiting mechanistic target of rapamycin (mTOR); however, other molecular mechanisms may also be involved. In this study, we examined the effects of metformin on the activity of receptor tyrosine kinases of the TAM (TYRO3, AXL, and MERTK) family, which have important roles in leukemia cell growth. The results indicated that metformin suppressed the in vitro growth of four leukemia cell lines, OCI/AML2, OCI/AML3, THP-1, and K562, in a dose-dependent manner, which corresponded to the downregulation of the expression and phosphorylation of AXL and inhibition of its downstream targets such as phosphorylation of STAT3. Furthermore, metformin augmented the suppressive effects of a small-molecule AXL inhibitor TP-0903 on the growth of OCI/AML3 and K562 cells and prevented doxorubicin-induced AXL activation in K562 cells, which induces chemoresistance in leukemia cells, thus potentiating doxorubicin anti-proliferative effects. Given that metformin also downregulated expression of TYRO3 and phosphorylation of MERTK, these findings indicate that anti-leukemic effects exerted by metformin could be partly due to the inhibition of TAM kinases. Thus, metformin has a clinical potential for patients with leukemia cells positive for AXL and the other TAM proteins as well as activated mTOR.