Hsu Jung-hsin, Shi Yijiang, Hu Liping, Fisher Myrna, Franke Thomas F, Lichtenstein Alan
Department of Medicine and Pathology, West LA VA-UCLA Medical Center and Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, CA 90073, USA.
Oncogene. 2002 Feb 21;21(9):1391-400. doi: 10.1038/sj.onc.1205194.
IL-6 is an established growth factor for multiple myeloma tumor cells, stimulating proliferative and survival responses. Recent work indicates that IL-6 can activate the AKT kinase in myeloma cells. Thus, to test a potential role for AKT in IL-6-induced cellular responses, we transfected myeloma cell lines with an active 'E40K' or dominant negative'PH AKT construct using an adenoviral vector. Transfection of the E40K into myeloma cells resulted in enhanced tumor cell growth and expression of the PH dominant negative AKT resulted in both inhibition of the IL-6-dependent proliferative response and a decrease in S phase distribution. While transfection of E40K protected myeloma cells from dexamethasone-induced apoptosis, the dominant negative PH had no effect on the ability of IL-6 to protect these cells from dexamethasone. These results clearly demonstrate that AKT activation is critical for the IL-6 proliferative response. In addition, although the level of AKT activation can regulate sensitivity to dexamethasone-induced apoptosis, additional cytokine-induced AKT-independent pathways can mediate IL-6 protection against dexamethasone. DOI: 10.1038/sj/onc/1205194
白细胞介素-6（IL-6）是一种公认的多发性骨髓瘤肿瘤细胞生长因子，可刺激增殖和存活反应。最近的研究表明，IL-6可激活骨髓瘤细胞中的AKT激酶。因此，为了测试AKT在IL-6诱导的细胞反应中的潜在作用，我们使用腺病毒载体将活性“E40K”或显性负性“PH AKT”构建体转染到骨髓瘤细胞系中。将E40K转染到骨髓瘤细胞中导致肿瘤细胞生长增强，而转染显性负性PH AKT则导致IL-6依赖性增殖反应受到抑制，S期分布减少。虽然转染E40K可保护骨髓瘤细胞免受地塞米松诱导的凋亡，但显性负性PH对IL-6保护这些细胞免受地塞米松影响的能力没有作用。这些结果清楚地表明，AKT激活对于IL-6增殖反应至关重要。此外，虽然AKT激活水平可调节对地塞米松诱导凋亡的敏感性，但其他细胞因子诱导的不依赖AKT的途径可介导IL-6对糖皮质激素的保护作用。DOI: 10.1038/sj/onc/1205194
