Insulin-like growth factor 2 expression modulates Taxol resistance and is a candidate biomarker for reduced disease-free survival in ovarian cancer.
Insulin-like growth factor 2 expression modulates Taxol resistance and is a candidate biomarker for reduced disease-free survival in ovarian cancer.
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DOI：
10.1158/1078-0432.ccr-09-3233
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发表时间：
2010-06-01
期刊：
影响因子：
--
通讯作者：
Horwitz SB
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文献类型：
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作者：
Huang GS;Brouwer-Visser J;Ramirez MJ;Kim CH;Hebert TM;Lin J;Arias-Pulido H;Qualls CR;Prossnitz ER;Goldberg GL;Smith HO;Horwitz SB
本研究旨在探讨胰岛素样生长因子（IGF）信号通路在卵巢癌细胞对紫杉醇反应中的作用，并评估该通路在人卵巢上皮性肿瘤中的意义。使用磷酸化AKT特异性抗体评价紫杉醇处理对A2780卵巢癌细胞中AKT活化的影响。为了研究卵巢癌细胞的耐药表型，我们从卵巢癌细胞系HEY中筛选出一株紫杉醇耐药细胞系HEY-T30。通过实时PCR测量IGF 2表达。使用IGF 1 R抑制剂NVP-AEW 541和IGF 2 siRNA来评估IGF途径抑制对增殖和紫杉醇敏感性的影响。IGF 2蛋白表达通过免疫组织化学方法在115例上皮性卵巢肿瘤中进行评估，并使用卡方或Fisher精确检验分析其与临床/病理因素的关系。采用考克斯回归分析研究IGF 2表达对生存率的影响。紫杉醇诱导的AKT磷酸化需要IGF 1 R酪氨酸激酶活性，并与IGF 2的上调有关。与敏感细胞相比，耐药细胞具有更高的IGF 2表达，IGF途径抑制恢复了对紫杉醇的敏感性。IGF 2高表达与肿瘤的晚期（p<0.001）和分级（p<0.01）相关，并降低无病生存率（p<0.05）。IGF 2调节紫杉醇耐药性，肿瘤IGF 2表达是上皮性卵巢肿瘤的候选预后生物标志物。IGF通路抑制剂可使耐药卵巢癌细胞对紫杉醇敏感。这些新的发现表明，IGF 2代表了卵巢癌的治疗靶点，特别是在紫杉醇耐药的情况下。
This study was undertaken to examine the role of the insulin-like growth factor (IGF) signaling pathway in the response of ovarian cancer cells to Taxol and to evaluate the significance of this pathway in human epithelial ovarian tumors. The effect of Taxol treatment on AKT activation in A2780 ovarian carcinoma cells was evaluated using antibodies specific for phosphorylated AKT. To study the drug-resistant phenotype, we developed a Taxol-resistant cell line, HEY-T30, derived from HEY ovarian carcinoma cells. IGF2 expression was measured by real-time PCR. An IGF1R inhibitor, NVP-AEW541, and IGF2 siRNA were used to evaluate the effect of IGF pathway inhibition on proliferation and Taxol sensitivity. IGF2 protein expression was evaluated by immunohistochemistry in 115 epithelial ovarian tumors, and analyzed in relation to clinical/pathologic factors using the Chi-square or Fisher’s exact tests. The influence of IGF2 expression on survival was studied with Cox regression. Taxol-induced AKT phosphorylation required IGF1R tyrosine kinase activity and was associated with upregulation of IGF2. Resistant cells had higher IGF2 expression compared with sensitive cells, and IGF pathway inhibition restored sensitivity to Taxol. High IGF2 tumor expression correlated with advanced stage (p<0.001) and tumor grade (p<0.01), and reduced disease-free survival (p<0.05). IGF2 modulates Taxol resistance, and tumor IGF2 expression is a candidate prognostic biomarker in epithelial ovarian tumors. IGF pathway inhibition sensitizes drug-resistant ovarian carcinoma cells to Taxol. Such novel findings suggest that IGF2 represents a therapeutic target in ovarian cancer, particularly in the setting of Taxol resistance.