Expression of insulin receptor isoform A and insulin-like growth factor-1 receptor in human acute myelogenous leukemia: effect of the dual-receptor inhibitor BMS-536924 in vitro.
Expression of insulin receptor isoform A and insulin-like growth factor-1 receptor in human acute myelogenous leukemia: effect of the dual-receptor inhibitor BMS-536924 in vitro.
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DOI：
10.1158/0008-5472.can-09-0511
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发表时间：
2009-10-01
期刊：
影响因子：
11.2
通讯作者：
Kaufmann SH
中科院分区：
文献类型：
--
作者：
Wahner Hendrickson AE;Haluska P;Schneider PA;Loegering DA;Peterson KL;Attar R;Smith BD;Erlichman C;Gottardis M;Karp JE;Carboni JM;Kaufmann SH
胰岛素受体（IR）和胰岛素样生长因子-1（IGF 1）受体（IGF 1 R）是参与正常和肿瘤上皮细胞中促有丝分裂和抗凋亡信号传导的受体酪氨酸激酶。在本研究中，免疫印迹和RT-PCR证实IGF 1 R和IR亚型A在急性髓细胞性白血病（AML）细胞系以及>80%的临床AML分离株中表达。用胰岛素治疗增强了通过Akt和MEK 1/2途径的信号传导以及血清饥饿的AML细胞系的存活。相反，BMS-536924（一种正在进行临床前试验的双重IGF 1 R/IR激酶抑制剂）治疗可抑制组成型受体磷酸化以及通过MEK 1/2和Akt的下游信号传导。这些变化抑制增殖，并在某些AML细胞系中，在亚微摩尔浓度下诱导细胞凋亡。同样，BMS-536924在体外抑制CD 34+临床AML样本中的白血病集落形成。总的来说，这些结果不仅表明IGF 1 R和IR亚型A的表达在AML中是常见的，而且还表明来自这些受体的信号传导的中断抑制了临床AML分离物中的增殖。因此，有必要进一步研究IGF 1 R/IR轴作为AML的潜在治疗靶点。
The insulin receptor (IR) and insulin-like growth factor-1 (IGF1) receptor (IGF1R) are receptor tyrosine kinases that participate in mitogenic and antiapoptotic signaling in normal and neoplastic epithelia. In the present study, immunoblotting and RT-PCR demonstrated expression of IGF1R and IR isoform A in acute myelogenous leukemia (AML) cell lines as well as >80% of clinical AML isolates. Treatment with insulin enhanced signaling through the Akt and MEK1/2 pathways as well as survival of serum-starved AML cell lines. Conversely, treatment with BMS-536924, a dual IGF1R/IR kinase inhibitor that is undergoing preclinical testing, inhibited constitutive receptor phosphorylation as well as downstream signaling through MEK1/2 and Akt. These changes inhibited proliferation and, in some AML cell lines, induced apoptosis at submicromolar concentrations. Likewise, BMS-536924 inhibited leukemic colony formation in CD34+ clinical AML samples in vitro. Collectively, these results not only indicate that expression of IGF1R and IR isoform A is common in AML, but also demonstrate that interruption of signaling from these receptors inhibits proliferation in clinical AML isolates. Accordingly, further investigation of IGF1R/IR axis as a potential therapeutic target in AML appears warranted.