Aberrant nuclear accumulation of glycogen synthase kinase-3β in human pancreatic cancer:: Association with kinase activity and tumor dedifferentiation
Aberrant nuclear accumulation of glycogen synthase kinase-3β in human pancreatic cancer:: Association with kinase activity and tumor dedifferentiation
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DOI：
10.1158/1078-0432.ccr-06-0196
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发表时间：
2006-09-01
影响因子：
11.5
通讯作者：
Billadeau, Daniel D.
中科院分区：
文献类型：
--
作者：
Ougolkov, Andrei V.;Fernandez-Zapico, Martin E.;Billadeau, Daniel D.
目的：我们最近证明，糖原合酶激酶 3 (GSK-3) beta 可调节核因子 kappa B (NF-kappa B) 介导的体外胰腺癌细胞存活和增殖。我们的目的是确定 GSK-3 β 在胰腺癌细胞中的定位，并评估体内 GSK-3 抑制的抗肿瘤作用，以提高我们对 GSK-3 β 影响胰腺癌中 NF-κ B 活性的机制的理解。 实验设计：进行免疫组织化学和胞质/核分级分离以确定 GSK-3 β 在人胰腺肿瘤中的定位。我们使用肿瘤再生延迟测定、蛋白质印迹、溴脱氧尿苷掺入和末端脱氧核苷酸转移酶介导的 dUTP 缺口末端标记，研究了 GSK-3 抑制对已建立的 CAPAN2 肿瘤异种移植物中肿瘤生长、癌细胞增殖和存活的影响。结果：我们在胰腺癌细胞系和 122 个（51%）人胰腺细胞系中的 62 个（51%）人胰腺细胞系中发现 GSK-3 β 的核积聚。腺癌。 GSK-3β核积累与人胰腺癌去分化显着相关。我们发现活性 GSK-3 可以在胰腺癌细胞的细胞核中积累，并且抑制 GSK-3 激酶活性可以通过细胞核内的蛋白酶体降解来抑制其在细胞核中的积累。最后，我们发现抑制 GSK-3 可以抑制体内胰腺肿瘤的生长，并降低已建立的肿瘤异种移植物中 NF-κ B 介导的胰腺癌细胞的存活和增殖。结论：我们的结果显示了 GSK-3 抑制的体内抗肿瘤作用，确定 GSK-3 核积累是低分化胰腺腺癌的标志，并为 GSK-3 β 调节胰腺中 NF-κ B 活性的机制提供了新的见解。癌症。
Purpose: We have shown recently that glycogen synthase kinase-3 (GSK-3) beta regulates nuclear factor-kappa B (NF-kappa B) - mediated pancreatic cancer cell survival and proliferation in vitro. Our objective was to determine the localization of GSK-3 beta in pancreatic cancer cells and assess the antitumor effect of GSK-3 inhibition in vivo to improve our understanding of the mechanism by which GSK-3 beta affects NF-kappa B activity in pancreatic cancer.Experimental Design: Immunohistochemistry and cytosolic/nuclear fractionation were done to determine the localization of GSK-3 beta in human pancreatic tumors. We studied the effect of GSK-3 inhibition on tumor growth, cancer cell proliferation, and survival in established CAPAN2 tumor xenografts using a tumor regrowth delay assay, Western blotting, bromodeoxyuridine incorporation, and terminal deoxynucleotidyl transferase - mediated dUTP nick end labeling.Results: We found nuclear accumulation of GSK-3 beta in pancreatic cancer cell lines and in 62 of 122 (51%) human pancreatic adenocarcinomas. GSK-3 beta nuclear accumulation is significantly correlated with human pancreatic cancer dedifferentiation. We have found that active GSK-3 can accumulate in the nucleus of pancreatic cancer cells and that inhibition of GSK-3 kinase activity represses its nuclear accumulation via proteasomal degradation within the nucleus. Lastly, we have found that inhibition of GSK-3 arrests pancreatic tumor growth in vivo and decreases NF-kappa B-mediated pancreatic cancer cell survival and proliferation in established tumor xenografts.Conclusions: Our results show the antitumor effect of GSK-3 inhibition in vivo, identify GSK-3 nuclear accumulation as a hallmark of poorly differentiated pancreatic adenocarcinoma, and provide new insight into the mechanism by which GSK-3 beta regulates NF-kappa B activity in pancreatic cancer.