Leukocyte Elastase Inhibitor, the precursor of L-DNase II, inhibits apoptosis by interfering with caspase-8 activation.
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.
Padrón-Barthe
Laura
L
Centre de Recherches des Cordeliers, INSERM, U872, Paris, F-75006, France.
Courta
Jacqueline
J
Leprêtre
Chloé
C
Nagbou
Atf
A
Torriglia
Alicia
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053178:Caspase 6 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D061945:Caspase Inhibitors; D002402:Cathepsin D / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D004706:Endodeoxyribonucleases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding; D017434:Protein Structure, Tertiary
D061945:Caspase Inhibitors; D004706:Endodeoxyribonucleases; C019329:deoxyribonuclease II; D019272:Leukocyte Elastase; D053178:Caspase 6; D053181:Caspase 8; D002402:Cathepsin D