Tu Y, Gardner A, Lichtenstein A
Department of Medicine, West LA VA Medical Center, Los Angeles, California, 90073, USA.
Cancer Res. 2000 Dec 1;60(23):6763-70.
Interleukin 6 (IL-6) and insulin-like growth factor I (IGF-I) induce proliferative and antiapoptotic responses in multiple myeloma (MM) plasma cells. Because these cytokines may activate the phosphatidylinositol 3-kinase (PI 3-K)/AKT kinase pathway in other cell types, we investigated the role of PI 3-K/AKT in MM cell responses. IGF-I effectively activated PI 3-K in 8226 and OCI-My5 MM cells, but IL-6 was ineffective. However, IL-6 successfully activated PI 3-K in AF-10 MM cells and IL-6-dependent MH.60 plasmacytoma/hybridoma cells. IGF-I also successfully activated PI 3-K in four of four MM patient specimens, and IL-6 activated PI 3-K in three of four specimens. Inhibition of PI 3-K activity with wortmannin or Ly294002 blocked the antiapoptotic effect of IGF-I and the proliferative effect of IL-6 in the myeloma cell lines. Furthermore, a dominant negative PI 3-K construct, expressed in AF-10 cells by adenoviral infection, also significantly inhibited the IL-6 proliferative response in MM cells. In correlation with activation of PI 3-K, IGF-I also effectively activated the AKT kinase in 8226 and OCI-My5 cells, and IL-6 activated AKT in AF-10 and MH.60 cells. However, although incapable of activating PI 3-K in 8226 and OCI-My5 cells, IL-6 successfully activated AKT in these MM lines, suggesting PI 3-K-independent mechanisms of AKT activation. The prevention of a myeloma cell proliferative response resulting from inhibition of PI 3-K activity was not associated with an inhibition of IL-6-dependent extracellular signal-regulated kinase (ERK) activation. These results support a role for the PI 3-K/AKT pathway in cytokine-dependent responses in myeloma cells, which is independent of any activation of the ERK pathway.
白细胞介素6（IL-6）和胰岛素样生长因子I（IGF-I）可诱导多发性骨髓瘤（MM）浆细胞发生增殖和抗凋亡反应。由于这些细胞因子可能在其他细胞类型中激活磷脂酰肌醇3激酶（PI 3-K）/AKT激酶途径，我们研究了PI 3-K/AKT在MM细胞反应中的作用。IGF-I可有效激活8226和OCI-My5 MM细胞中的PI 3-K，但IL-6无效。然而，IL-6成功激活了AF-10 MM细胞和IL-6依赖性MH.60浆细胞瘤/杂交瘤细胞中的PI 3-K。IGF-I还成功激活了4例MM患者标本中的PI 3-K，IL-6激活了4例标本中的3例。用渥曼青霉素或Ly294002抑制PI 3-K活性可阻断IGF-I的抗凋亡作用和IL-6在骨髓瘤细胞系中的增殖作用。此外，通过腺病毒感染在AF-10细胞中表达的显性负性PI 3-K构建体也显著抑制了MM细胞中IL-6的增殖反应。与PI 3-K的激活相关，IGF-I还可有效激活8226和OCI-My5细胞中的AKT激酶，IL-6激活AF-10和MH.60细胞中的AKT。然而，尽管IL-6在8226和OCI-My5细胞中无法激活PI 3-K，但它成功激活了这些MM细胞系中的AKT，提示存在PI 3-K非依赖性的AKT激活机制。抑制PI 3-K活性导致的骨髓瘤细胞增殖反应的阻断与IL-6依赖性细胞外信号调节激酶（ERK）激活的抑制无关。这些结果支持PI 3-K/AKT途径在骨髓瘤细胞细胞因子依赖性反应中的作用，该作用独立于ERK途径的任何激活。
