Nuutinen Ulla, Postila Ville, Mättö Mikko, Eeva Jonna, Ropponen Antti, Eray Mine, Riikonen Pekka, Pelkonen Jukka
Department of Clinical Microbiology, University of Kuopio, Harjulantie 1 C, 70210 Kuopio, Finland.
Exp Cell Res. 2006 Feb 1;312(3):322-30. doi: 10.1016/j.yexcr.2005.10.023. Epub 2005 Nov 23.
Glucocorticoids are commonly used in the treatment of various lymphoid malignancies. In the present study, we show that dexamethasone (Dex) induced depolarization of mitochondrial membrane, release of cytochrome c and DNA fragmentation in a human follicular lymphoma cell line, HF28RA. New protein synthesis was required before Dex-induced mitochondrial changes, and the kinetics of the apoptotic events correlated with the upregulation of the Bim protein. Furthermore, we studied whether specific inhibitors of known survival pathways would potentiate Dex-induced apoptosis. Our results show that inhibition of PKC and ERK pathways had no effect on apoptosis. In contrast, inhibition of PI3-kinase or Akt markedly enhanced Dex-induced apoptosis. The enhancement was seen at the mitochondrial level, and the kinetics of apoptosis was notably accelerated. In addition, inhibition of PI3-kinase did not alter levels of Bax, Bcl-2, Bcl-X(L) or Bim proteins in mitochondria but caused translocation of the pro-apoptotic protein Bad to mitochondria. However, inhibition of PI3-kinase-Akt pathway and subsequent translocation of Bad to mitochondria did not induce apoptosis itself. Based on these results and our current understanding of Bim and Bad action, it seems that both proteins play a synergistic role in this process. Thus, these results indicate that inhibitors of PI3-kinase-Akt pathway might be combined in future with glucocorticoids to improve the treatment of lymphoid malignancies.
糖皮质激素常用于治疗各种淋巴系统恶性肿瘤。在本研究中，我们发现地塞米松（Dex）可诱导人滤泡性淋巴瘤细胞系HF28RA的线粒体膜去极化、细胞色素c释放及DNA片段化。Dex诱导线粒体变化之前需要新的蛋白质合成，且凋亡事件的动力学与Bim蛋白的上调相关。此外，我们研究了已知生存途径的特异性抑制剂是否会增强Dex诱导的凋亡。我们的结果表明，抑制PKC和ERK途径对凋亡无影响。相反，抑制PI3激酶或Akt可显著增强Dex诱导的凋亡。这种增强作用在线粒体水平可见，且凋亡动力学明显加快。此外，抑制PI3激酶不会改变线粒体中Bax、Bcl-2、Bcl-X(L)或Bim蛋白的水平，但会导致促凋亡蛋白Bad转位至线粒体。然而，抑制PI3激酶-Akt途径及随后Bad转位至线粒体本身并不会诱导凋亡。基于这些结果以及我们目前对Bim和Bad作用的理解，似乎这两种蛋白在此过程中发挥协同作用。因此，这些结果表明PI3激酶-Akt途径抑制剂未来可能与糖皮质激素联合使用，以改善淋巴系统恶性肿瘤的治疗。
