Liu Ying, Perdreau Sophie A, Chatterjee Payel, Wang Linan, Kuan Shih-Fan, Duensing Anette
Molecular Virology Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, Pennsylvania15213, USA.
Cancer Res. 2008 Nov 1;68(21):9015-23. doi: 10.1158/0008-5472.CAN-08-1935.
Gastrointestinal stromal tumors (GIST) are caused by activating mutations in the KIT or platelet-derived growth factor receptor alpha receptor tyrosine kinase genes. Approximately 85% of GIST patients treated with imatinib mesylate achieve disease stabilization, however, often in the presence of residual tumor masses. Complete remissions are rare and a substantial proportion of patients develop resistance to imatinib. Our study was designed to determine whether imatinib-associated responses may account for these clinical findings. We report here that imatinib stimulates cellular quiescence in a proportion of GIST cells as evidenced by up-regulation of the CDK inhibitor p27(Kip1), loss of cyclin A, and reduced BrdUrd incorporation. Mechanistically, these events are associated with an imatinib-induced modulation of the APC/CDH1 signaling axis. Specifically, we provide evidence that imatinib down-regulates SKP2 and that this event is associated with increased nuclear CDH1, an activator of the APC that has been shown to regulate SKP2 stability. We also show that those GIST cells that do not undergo apoptosis in response to imatinib overexpress nuclear p27(Kip1), indicating that they have withdrawn from the cell cycle and are quiescent. Lastly, we provide evidence that a fraction of primary GISTs with high SKP2 expression levels may have an increased risk of disease progression. Taken together, our results support a model in which GIST cells that do not respond to imatinib by apoptosis are removed from the proliferative pool by entering quiescence through modulation of the APC/CDH1-SKP2-p27(Kip1) signaling axis. These results encourage further studies to explore compounds that modulate this pathway as antitumor agents in GISTs.
胃肠道间质瘤（GIST）由KIT或血小板衍生生长因子受体α受体酪氨酸激酶基因的激活突变引起。约85%接受甲磺酸伊马替尼治疗的GIST患者病情稳定，然而，通常存在残留肿瘤块。完全缓解罕见，且相当一部分患者会对伊马替尼产生耐药性。我们的研究旨在确定伊马替尼相关反应是否可解释这些临床发现。我们在此报告，伊马替尼可刺激一部分GIST细胞进入静息状态，这表现为细胞周期蛋白依赖性激酶抑制剂p27（Kip1）上调、细胞周期蛋白A丢失以及溴脱氧尿苷掺入减少。从机制上讲，这些事件与伊马替尼诱导的APC/CDH1信号轴调节有关。具体而言，我们提供证据表明伊马替尼下调SKP2，且该事件与核内CDH1增加有关，CDH1是APC的激活剂，已被证明可调节SKP2稳定性。我们还表明，那些对伊马替尼无凋亡反应的GIST细胞过表达核内p27（Kip1），表明它们已退出细胞周期并处于静息状态。最后，我们提供证据表明，一部分SKP2表达水平高的原发性GIST可能有疾病进展风险增加的情况。综上所述，我们的结果支持这样一种模型，即对伊马替尼无凋亡反应的GIST细胞通过调节APC/CDH1 - SKP2 - p27（Kip1）信号轴进入静息状态，从而从增殖池中被清除。这些结果鼓励进一步研究，以探索调节该途径的化合物作为GIST的抗肿瘤药物。
