Department of Urology, The University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
J Cell Sci. 2010 Mar 15;123(Pt 6):861-70. doi: 10.1242/jcs.060475. Epub 2010 Feb 16.
Glycogen synthase kinase 3 beta (GSK-3beta) is constantly active in cells and its activity increases after serum deprivation, indicating that GSK-3beta might play a major role in cell survival under serum starvation. In this study, we attempted to determine how GSK-3beta promotes cell survival after serum depletion. Under full culture conditions (10% FBS), GSK-3beta inhibition with chemical inhibitors or siRNAs failed to induce cell death in human prostate cancer cells. By contrast, under conditions of serum starvation, a profound necrotic cell death was observed as evidenced by cellular morphologic features and biochemical markers. Further analysis revealed that GSK-3beta-inhibition-induced cell death was in parallel with an extensive autophagic response. Interestingly, blocking the autophagic response switched GSK-3beta-inhibition-induced necrosis to apoptotic cell death. Finally, GSK-3beta inhibition resulted in a remarkable elevation of Bif-1 protein levels, and silencing Bif-1 expression abrogated GSK-3beta-inhibition-induced autophagic response and cell death. Taken together, our study suggests that GSK-3beta promotes cell survival by modulating Bif-1-dependent autophagic response and cell death.
糖原合酶激酶 3β（GSK-3β）在细胞中持续活跃，其活性在血清剥夺后增加，表明 GSK-3β 可能在血清饥饿时细胞存活中起主要作用。在本研究中，我们试图确定 GSK-3β 如何在血清耗尽后促进细胞存活。在完全培养条件下（10% FBS），化学抑制剂或 siRNA 抑制 GSK-3β 未能诱导人前列腺癌细胞死亡。相比之下，在血清饥饿条件下，观察到明显的坏死性细胞死亡，这可通过细胞形态特征和生化标志物证实。进一步分析表明，GSK-3β 抑制诱导的细胞死亡与广泛的自噬反应平行。有趣的是，阻断自噬反应将 GSK-3β 抑制诱导的坏死转变为凋亡细胞死亡。最后，GSK-3β 抑制导致 Bif-1 蛋白水平显著升高，沉默 Bif-1 表达可消除 GSK-3β 抑制诱导的自噬反应和细胞死亡。总之，我们的研究表明，GSK-3β 通过调节 Bif-1 依赖性自噬反应和细胞死亡来促进细胞存活。
