Department of Medicine, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Cancer Res. 2011 Dec 1;71(23):7291-300. doi: 10.1158/0008-5472.CAN-11-1715. Epub 2011 Oct 10.
All cancer cells require increased nutrient uptake to support proliferation. In this study, we investigated the signals that govern glucose uptake in B-cell lymphomas and determined that the inhibitor of NF-κB-kinase β (IKKβ) induced glucose transporter-1 (GLUT1) membrane trafficking in both viral and spontaneous B-cell lymphomas. IKKβ induced AKT activity, whereas IKKβ-driven NF-κB transcription was required for GLUT1 surface localization downstream of AKT. Activated NF-κB promoted AKT-mediated phosphorylation of the GLUT1 regulator, AKT substrate of 160kD (AS160), but was not required for AKT phosphorylation of the mTOR regulator Tuberous Sclerosis 2 (TSC2). In Epstein-Barr virus-transformed B cells, NF-κB inhibition repressed glucose uptake and induced caspase-independent cell death associated with autophagy. After NF-κB inhibition, an alternate carbon source ameliorated both autophagy and cell death, whereas autophagy inhibitors specifically accelerated cell death. Taken together, the results indicate that NF-κB signaling establishes a metabolic program supporting proliferation and apoptosis resistance by driving glucose import.
所有癌细胞都需要增加营养物质的摄取来支持增殖。在这项研究中，我们研究了控制 B 细胞淋巴瘤中葡萄糖摄取的信号，结果表明，NF-κB-激酶β（IKKβ）抑制剂在病毒和自发性 B 细胞淋巴瘤中诱导葡萄糖转运蛋白-1（GLUT1）的膜转运。IKKβ诱导 AKT 活性，而 IKKβ 驱动的 NF-κB 转录是 AKT 下游 GLUT1 表面定位所必需的。激活的 NF-κB 促进 AKT 介导的 GLUT1 调节因子、160kD 的 AKT 底物（AS160）的磷酸化，但对于 AKT 对 mTOR 调节因子结节性硬化症 2（TSC2）的磷酸化不是必需的。在 Epstein-Barr 病毒转化的 B 细胞中，NF-κB 抑制抑制葡萄糖摄取并诱导与自噬相关的 caspase 非依赖性细胞死亡。NF-κB 抑制后，替代碳源改善了自噬和细胞死亡，而自噬抑制剂则特异性地加速了细胞死亡。综上所述，这些结果表明，NF-κB 信号通过驱动葡萄糖摄取来建立支持增殖和抗凋亡的代谢程序。
