Deregulated GSK3β activity in colorectal cancer:: Its association with tumor cell survival and proliferation
Deregulated GSK3β activity in colorectal cancer:: Its association with tumor cell survival and proliferation
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DOI：
10.1016/j.bbrc.2005.07.041
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发表时间：
2005-09-09
影响因子：
3.1
通讯作者：
Minamoto, T
中科院分区：
文献类型：
--
作者：
Shakoori, A;Ougolkov, A;Minamoto, T
据报道，糖原合成酶激酶3 β (GSK3 β)具有相反的作用，一方面抑制Wnt/ β -catenin信号传导，另一方面通过nf - κ B途径维持细胞存活和增殖。本研究旨在阐明GSK3 β在人类癌症中的作用。在结肠癌细胞系和结直肠癌患者中，肿瘤细胞中GSK3 β的表达水平及其活性形式的量高于正常细胞；这些发现与肿瘤细胞中β -连环蛋白癌蛋白的核积累无关。通过磷酸化抑制GSK3 β活性在结直肠癌中存在缺陷，但在非肿瘤细胞和组织中保留。值得注意的是，化学抑制剂抑制GSK3 β活性和RNA干扰GSK3 β表达可诱导体外结肠癌细胞凋亡和增殖减弱。我们的研究结果证明了GSK3 β在肿瘤细胞存活和增殖中的作用，而不是其作为肿瘤抑制因子的预测作用，并且有理由提出该激酶作为结直肠癌的潜在治疗靶点。(c) 2005爱思唯尔公司版权所有。
Glycogen synthase kinase 3 beta (GSK3 beta) reportedly has opposing roles, repressing Wnt/beta-catenin signaling on the one hand but maintaining cell survival and proliferation through the NF-kappa B pathway on the other. The present investigation was undertaken to clarify the roles of GSK3 beta in human cancer. In colon cancer cell lines and colorectal cancer patients, levels of GSK3 beta expression and amounts of its active form were higher in tumor cells than in their normal counterparts; these findings were independent of nuclear accumulation of beta-catenin oncoprotein in the tumor cells. Inhibition of GSK3 beta activity by phosphorylation was defective in colorectal cancers but preserved in non-neoplastic cells and tissues. Strikingly, inhibition of GSK3 beta activity by chemical inhibitors and its expression by RNA interference targeting GSK3 beta induced apoptosis and attenuated proliferation of colon cancer cells in vitro. Our findings demonstrate an unrecognized role of GSK3 beta in tumor cell survival and proliferation other than its predicted role as a tumor suppressor, and warrant proposing this kinase as a potential therapeutic target in colorectal cancer. (c) 2005 Elsevier Inc. All rights reserved.