Glycogen synthase kinase-3β participates in nuclear factor κB-mediated gene transcription and cell survival in pancreatic cancer cells
Glycogen synthase kinase-3β participates in nuclear factor κB-mediated gene transcription and cell survival in pancreatic cancer cells
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DOI：
10.1158/0008-5472.can-04-3642
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发表时间：
2005-03-15
期刊：
影响因子：
11.2
通讯作者：
Billadeau, DD
中科院分区：
文献类型：
--
作者：
Ougolkov, AV;Fernandez-Zapico, ME;Billadeau, DD
最近对糖原合成酶激酶-3 β (GSK-3 β)缺陷小鼠胚胎成纤维细胞的研究表明，GSK-3 β正调控核因子κ B （NF κ B）介导的基因转录。由于NF κ B被认为参与胰腺癌细胞增殖和存活途径，我们研究了GSK-3 β在调节这些细胞过程中的作用。在此，我们发现胰腺癌细胞含有活性GSK-3 β，并且使用小分子抑制剂或通过RNA干扰GSK-3 β的基因耗尽来抑制GSK-3激酶活性导致癌细胞增殖和存活降低。在机制上，我们发现GSK-3 β影响NF κ B介导的基因转录在I κ pa激酶复合物的远端，因为只有NF κ B亚基p65/p50的异位表达，而I κ pa激酶β组成型活性突变体不能挽救与GSK-3 β抑制相关的细胞增殖和存活下降。综上所述，我们的研究结果同时确定了GSK-3在癌细胞存活和增殖中的先前未被认识到的作用，并表明GSK-3 β是治疗胰腺癌的潜在治疗靶点。
Recent studies using glycogen synthase kinase-3 beta (GSK-3 beta)-deficient mouse embryonic fibroblasts suggest that GSK-3 beta positively regulates nuclear factor kappa B (NF kappa B)-mediated gene transcription. Because NF kappa B is suggested to participate in cell proliferation and survival pathways in pancreatic cancer, we investigated the role of GSK-3 beta in regulating these cellular processes. Herein, we show that pancreatic cancer cells contain a pool of active GSK-3 beta and that pharmacologic inhibition of GSK-3 kinase activity using small molecule inhibitors or genetic depletion of GSK-3 beta by RNA interference leads to decreased cancer cell proliferation and survival. Mechanistically, we show that GSK-3 beta influences NF kappa B-mediated gene transcription at a point distal to the I kappa, kinase complex, as only ectopic expression of the NF kappa B subunits p65/p50, but not an I kappa, kinase beta constitutively active mutant, could rescue the decreased cellular proliferation and survival associated with GSK-3 beta inhibition. Taken together, our results simultaneously identify a previously unrecognized role for GSK-3 in cancer cell survival and proliferation and suggest GSK-3 beta as a potential therapeutic target in the treatment of pancreatic cancer.