Role of Insulin-Like Growth Factor Binding Protein 2 in Lung Adenocarcinoma IGF-Independent Antiapoptotic Effect Via Caspase-3
Role of Insulin-Like Growth Factor Binding Protein 2 in Lung Adenocarcinoma IGF-Independent Antiapoptotic Effect Via Caspase-3
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DOI：
10.2353/ajpath.2010.090500
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发表时间：
2010-04-01
影响因子：
6
通讯作者：
Ishikawa, Yuichi
中科院分区：
文献类型：
--
作者：
Migita, Toshiro;Narita, Tadahito;Ishikawa, Yuichi
胰岛素样生长因子（IGF）信号在细胞增殖和有丝分裂中起着关键作用。分泌的IGF结合蛋白（igfbp）是IGF生物利用度的重要调节剂；然而，它们在细胞内的功能仍然难以捉摸。我们试图评估肺腺癌细胞内IGFBP-2的抗凋亡特性。IGFBP-2过表达导致procaspase-3表达降低；然而，它不影响IGF受体或其下游靶点的磷酸化状态，包括Akt和细胞外信号调节激酶。喜树碱诱导的NCI-H522细胞凋亡被IGFBP-2过表达显著抑制。相反，在NCI-H522细胞中，使用小干扰RNA选择性敲除IGFBP-2导致procaspase-3表达增加，并对喜树碱诱导的凋亡增敏。LY294002是一种磷脂酰肌醇3-激酶抑制剂，与喜树碱联合使用可降低IGFBP-2水平，增强细胞凋亡。免疫组化结果显示，肺腺癌细胞内IGFBP-2的表达高于正常上皮细胞。细胞内IGFBP-2和procaspase-3以互斥的方式表达。这些发现表明，细胞内IGFBP-2调节caspase-3的表达，并参与了独立于IGF的细胞凋亡抑制作用。因此，IGFBP-2可能提供一个新的治疗靶点，并作为肺腺癌的抗凋亡生物标志物。（Am J. Pathol, 2010, 176:1756-1766; DOI: 10.2353/ajpath.2010.090500）
Insulin-like growth factor (IGF) signaling plays a pivotal role in cell proliferation and mitogenesis. Secreted IGF-binding proteins (IGFBPs) are important modulators of IGF bioavailability; however, their intracellular functions remain elusive. We sought to assess the antiapoptotic properties of intracellular IGFBP-2 in lung adenocarcinomas. IGFBP-2 overexpression resulted in a decrease in procaspase-3 expression; however, it did not influence the phosphorylation status of either IGF receptor or its downstream targets, including Akt and extracellular signal-regulated kinase. Apoptosis induced by camptothecin was significantly inhibited by IGFBP-2 overexpression in NCI-H522 cells. Conversely, selective knockdown of IGFBP-2 using small-interfering RNA resulted in an increase in procaspase-3 expression and sensitization to camptothecin-induced apoptosis in NCI-H522 cells. LY294002, an inhibitor of phosphatidylinositol 3-kinase, caused a decrease in IGFBP-2 levels and enhanced apoptosis in combination with camptothecin. Immunohistochemistry demonstrated that intracellular IGFBP-2 was highly expressed in lung adenocarcinomas compared with normal epithelium. Intracellular IGFBP-2 and procaspase-3 were expressed in a mutually exclusive manner. These findings suggest that intracellular IGFBP-2 regulates caspase-3 expression and contributes to the inhibitory effect on apoptosis independent of IGF. IGFBP-2, therefore, may offer a novel therapeutic target and serve as an antiapoptotic biomarker for lung adenocarcinoma. (Am J. Pathol 2010, 176:1756-1766; DOI: 10.2353/ajpath.2010.090500)