Glycogen synthase kinase-3β, NF-κB signaling, and tumorigenesis of human osteosarcoma.
Glycogen synthase kinase-3β, NF-κB signaling, and tumorigenesis of human osteosarcoma.
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DOI：
10.1093/jnci/djs210
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发表时间：
2012-05-16
期刊：
影响因子：
--
通讯作者：
Kang T
中科院分区：
文献类型：
--
作者：
Tang QL;Xie XB;Wang J;Chen Q;Han AJ;Zou CY;Yin JQ;Liu DW;Liang Y;Zhao ZQ;Yong BC;Zhang RH;Feng QS;Deng WG;Zhu XF;Zhou BP;Zeng YX;Shen JN;Kang T
糖原合成酶激酶-3 β（GSK-3β）是一种丝氨酸/苏氨酸蛋白激酶，根据肿瘤类型，可能作为肿瘤抑制因子或癌基因发挥作用。我们试图确定GSK-3β在骨肉瘤中的生物学功能，骨肉瘤是一种罕见的儿科癌症，迫切需要确定新的治疗靶点。我们使用细胞活力测定、集落形成测定和凋亡测定来分析GSK-3β表达改变在U2 OS、MG 63、SAOS 2、U2 OS/MTX 300和ZOS骨肉瘤细胞系中的作用。向裸小鼠（n = 5-8只小鼠/组）注射U2 OS/MTX 300和ZOS细胞，以评估GSK-3β在体内骨肉瘤生长中的作用，并评估抑制剂和/或抗癌药物对肿瘤生长的影响。我们使用抗体阵列、聚合酶链反应、蛋白质印迹和荧光素酶报告基因试验来确定GSK-3β抑制对核因子-κB（NF-κB）通路的影响。对来自骨肉瘤患者（n = 74）的原发肿瘤标本进行免疫化学以确定GSK-3β活性与总生存率的关系。具有低水平的无活性p-Ser 9-GSK-3β的骨肉瘤细胞比具有高水平的细胞更容易在体外形成集落和在体内形成肿瘤，并且其中GSK-3β已被沉默的细胞比亲本细胞形成更少的集落和更小的肿瘤。GSK-3β的沉默或药物抑制可导致骨肉瘤细胞凋亡。GSK-3β的抑制导致NF-κB B通路的抑制和NF-κ B介导的转录的减少。GSK-3β抑制剂、NF-κB抑制剂和化疗药物联合治疗可增加化疗药物的体外和体内有效性。骨肉瘤标本中GSK-3β和核NF-κB活性高的患者的中位总生存期（49.2个月）短于肿瘤中GSK-3β和NF-κB活性低的患者（109.2个月）。GSK-3β活性可能促进骨肉瘤肿瘤生长，针对GSK-3β和/或NF-κB通路的治疗可能是增强抗癌药物对骨肉瘤治疗活性的有效途径。
Glycogen synthase kinase-3β (GSK-3β), a serine/threonine protein kinase, may function as a tumor suppressor or an oncogene, depending on the tumor type. We sought to determine the biological function of GSK-3β in osteosarcoma, a rare pediatric cancer for which the identification of new therapeutic targets is urgent. We used cell viability assays, colony formation assays, and apoptosis assays to analyze the effects of altered GSK-3β expression in U2OS, MG63, SAOS2, U2OS/MTX300, and ZOS osteosarcoma cell lines. Nude mice (n = 5–8 mice per group) were injected with U2OS/MTX300, and ZOS cells to assess the role of GSK-3β in osteosarcoma growth in vivo and to evaluate the effects of inhibitors and/or anticancer drugs on tumor growth. We used an antibody array, polymerase chain reaction, western blotting, and a luciferase reporter assay to establish the effect of GSK-3β inhibition on the nuclear factor-κB (NF-κB) pathway. Immunochemistry was performed on primary tumor specimens from osteosarcoma patients (n = 74) to determine the relationship of GSK-3β activity with overall survival. Osteosarcoma cells with low levels of inactive p-Ser9-GSK-3β formed colonies in vitro and tumors in vivo more readily than cells with higher levels and cells in which GSK-3β had been silenced formed fewer colonies and smaller tumors than parental cells. Silencing or pharmacological inhibition of GSK-3β resulted in apoptosis of osteosarcoma cells. Inhibition of GSK-3β resulted in inhibition of the NF-κB pathway and reduction of NF-κB-mediated transcription. Combination treatments with GSK-3β inhibitors, NF-κB inhibitors, and chemotherapy drugs increased the effectiveness of chemotherapy drugs in vitro and in vivo. Patients whose osteosarcoma specimens had hyperactive GSK-3β, and nuclear NF-κB had a shorter median overall survival time (49.2 months) compared with patients whose tumors had inactive GSK-3β and NF-κB (109.2 months). GSK-3β activity may promote osteosarcoma tumor growth, and therapeutic targeting of the GSK-3β and/or NF-κB pathways may be an effective way to enhance the therapeutic activity of anticancer drugs against osteosarcoma.
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影响因子：
15.3
作者：
SCHRECK, R;MEIER, B;MANNEL, DN;DROGE, W;BAEUERLE, PA
通讯作者：
BAEUERLE, PA
影响因子：
24.5
作者：
Satoh, A;Shimosegawa, T;Toyota, T
通讯作者：
Toyota, T
影响因子：
50.3
作者：
Kang, Tiebang;Wei, Yongkun;Piwnica-Worms, Helen
通讯作者：
Piwnica-Worms, Helen
影响因子：
37.3
作者：
Mishra R
通讯作者：
Mishra R
影响因子：
4
作者：
Eliseev, RA;Zuscik, MJ;Rosier, RN
通讯作者：
Rosier, RN