IGFBP7 induces apoptosis of acute myeloid leukemia cells and synergizes with chemotherapy in suppression of leukemia cell survival.
IGFBP7 induces apoptosis of acute myeloid leukemia cells and synergizes with chemotherapy in suppression of leukemia cell survival.
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DOI：
10.1038/cddis.2014.268
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发表时间：
2014-06-26
影响因子：
9
通讯作者：
Smit L
中科院分区：
文献类型：
--
作者：
Verhagen HJ;de Leeuw DC;Roemer MG;Denkers F;Pouwels W;Rutten A;Celie PH;Ossenkoppele GJ;Schuurhuis GJ;Smit L
尽管化疗后的缓解率很高，但只有30-40%的急性髓性白血病（AML）患者在诊断后存活5年。这种极差的AML预后主要是由于化疗耐药导致的治疗失败。化疗抗性可由多种特征引起，包括替代信号传导途径的激活、细胞死亡的逃避或受体酪氨酸激酶如胰岛素生长因子-1受体（IGF-1 R）的激活。在这里，我们研究了胰岛素样生长因子结合蛋白7（IGFBP 7），一种肿瘤抑制因子和IGF-1 R轴的一部分，在AML中的作用。我们报告IGFBP 7使AML细胞对化疗诱导的细胞死亡敏感。此外，IGFBP 7的过表达以及重组人IGFBP 7的添加能够通过诱导G2细胞周期停滞和细胞凋亡来降低AML细胞的存活。这种作用主要不依赖于IGF-1 R的活化、Akt的活化和Erk的活化。重要的是，具有高IGFBP 7表达的AML患者比具有低IGFBP 7表达的患者具有更好的结果，表明IGFBP 7在AML的治疗和结果中的积极作用。总之，这表明IGFBP 7和化疗的组合可能潜在地克服传统的AML耐药性，从而可能改善AML患者的存活率。
Despite high remission rates after chemotherapy, only 30–40% of acute myeloid leukemia (AML) patients survive 5 years after diagnosis. This extremely poor prognosis of AML is mainly caused by treatment failure due to chemotherapy resistance. Chemotherapy resistance can be caused by various features including activation of alternative signaling pathways, evasion of cell death or activation of receptor tyrosine kinases such as the insulin growth factor-1 receptor (IGF-1R). Here we have studied the role of the insulin-like growth factor-binding protein-7 (IGFBP7), a tumor suppressor and part of the IGF-1R axis, in AML. We report that IGFBP7 sensitizes AML cells to chemotherapy-induced cell death. Moreover, overexpression of IGFBP7 as well as addition of recombinant human IGFBP7 is able to reduce the survival of AML cells by the induction of a G2 cell cycle arrest and apoptosis. This effect is mainly independent from IGF-1R activation, activated Akt and activated Erk. Importantly, AML patients with high IGFBP7 expression have a better outcome than patients with low IGFBP7 expression, indicating a positive role for IGFBP7 in treatment and outcome of AML. Together, this suggests that the combination of IGFBP7 and chemotherapy might potentially overcome conventional AML drug resistance and thus might improve AML patient survival.