Padrón-Barthe Laura, Courta Jacqueline, Leprêtre Chloé, Nagbou Atf, Torriglia Alicia
Centre de Recherches des Cordeliers, INSERM, U872, Paris, F-75006, France.
Biochim Biophys Acta. 2008 Oct;1783(10):1755-66. doi: 10.1016/j.bbamcr.2008.06.018. Epub 2008 Jul 8.
LEI (Leukocyte Elastase Inhibitor), the precursor of the pro-apoptotic molecule L-DNase II, belongs to the ovalbumin subgroup of serpins. Several serpins can inhibit apoptosis: the viral serpin Crm A inhibits Fas or TNFalpha-induced apoptosis, and overexpression of PAI-2 or PI-9 protects cells from TNFalpha or granzyme B induced apoptosis. We have previously shown that LEI overexpression protects cells from etoposide-induced apoptosis. The molecular reason of this anti-apoptotic activity is now investigated. We show that, in BHK-21 and HeLa cells, LEI anti-protease activity is essential for its anti-apoptotic effect. The protease inhibited is cathepsin D, released from the lysosome during etoposide treatment. Cathepsin D enhances caspase activity in the cell by cleaving procaspase-8 and LEI overexpression slows down this cleavage, protecting cells from apoptosis. This let us presume that high expression of LEI in tumor cells may reduce the efficiency of etoposide as a chemotherapeutic agent.
白细胞弹性蛋白酶抑制剂（LEI）是促凋亡分子L-DNase II的前体，属于丝氨酸蛋白酶抑制剂（serpins）的卵清蛋白亚组。几种丝氨酸蛋白酶抑制剂可以抑制细胞凋亡：病毒丝氨酸蛋白酶抑制剂Crm A可抑制Fas或TNFα诱导的细胞凋亡，PAI-2或PI-9的过表达可保护细胞免受TNFα或颗粒酶B诱导的细胞凋亡。我们之前已经表明，LEI的过表达可保护细胞免受依托泊苷诱导的细胞凋亡。现在我们研究这种抗凋亡活性的分子机制。我们发现，在BHK-21和HeLa细胞中，LEI的抗蛋白酶活性对其抗凋亡作用至关重要。被抑制的蛋白酶是组织蛋白酶D，它在依托泊苷处理期间从溶酶体中释放出来。组织蛋白酶D通过切割procaspase-8来增强细胞中的半胱天冬酶活性，而LEI的过表达减缓了这种切割，从而保护细胞免受凋亡。这使我们推测，肿瘤细胞中LEI的高表达可能会降低依托泊苷作为化疗药物的疗效。
