Stefanelli C, Bonavita F, Stanic I, Pignatti C, Farruggia G, Masotti L, Guarnieri C, Caldarera C M
Department of Biochemistry 'G. Moruzzi', University of Bologna, Via Irnerio 48, I-40126 Bologna, Italy.
Biochem J. 1998 Jun 15;332 ( Pt 3)(Pt 3):661-5. doi: 10.1042/bj3320661.
Recent investigations have indicated the involvement of proteasome in programmed cell death. The present studies show that although peptide aldehyde inhibitors of proteasome are by themselves weak inducers of apoptosis, they inhibit the apoptotic effect of the anticancer drug etoposide in rat thymocytes. Acetyl-Leu-Leu-norvalinal (LLnV-al) and other related peptide aldehydes inhibited the increase in caspase activity and DNA fragmentation that followed treatment with etoposide and their effect was related to their potency as proteasome inhibitors. To inhibit etoposide-induced apoptosis, LLnV-al must be present within 3 h of treatment with etoposide, in the same way as the inhibitor of protein synthesis cycloheximide must be. Etoposide caused a rapid accumulation of p53 protein that was not inhibited by LLnV-al, which was also a strong inducer of p53. Peptide aldehydes were also weak activators of caspase activity, suggesting that the same mechanism, i.e. the blocking of proteasome function, both triggers apoptosis and inhibits the effect of etoposide. These results are consistent with a model in which proteasome is selectively involved in the pathway used by etoposide to induce cell suicide.
最近的研究表明蛋白酶体参与程序性细胞死亡。目前的研究表明，虽然蛋白酶体的肽醛抑制剂本身是较弱的凋亡诱导剂，但它们能抑制抗癌药物依托泊苷对大鼠胸腺细胞的凋亡作用。乙酰 - 亮氨酸 - 亮氨酸 - 正缬氨酸醛（LLnV - al）和其他相关肽醛抑制了依托泊苷处理后半胱天冬酶活性的增加和DNA片段化，并且它们的作用与其作为蛋白酶体抑制剂的效力相关。为了抑制依托泊苷诱导的凋亡，LLnV - al必须在依托泊苷处理后3小时内存在，这与蛋白质合成抑制剂环己酰亚胺的情况相同。依托泊苷导致p53蛋白快速积累，而LLnV - al对此没有抑制作用，LLnV - al也是p53的强诱导剂。肽醛也是半胱天冬酶活性的弱激活剂，这表明相同的机制，即蛋白酶体功能的阻断，既触发凋亡又抑制依托泊苷的作用。这些结果与一种模型一致，即蛋白酶体选择性地参与依托泊苷诱导细胞自杀所使用的途径。
