TY - JOUR
T1 - Protease activation is required for glucocorticoid-induced apoptosis in chronic lymphocytic leukemic lymphocytes
AU - Chandra, Joya
AU - Gilbreath, Joyce
AU - Freireich, Emil J.
AU - Kliche, Kay Oliver
AU - Andreeff, Michael
AU - Keating, Michael
AU - McConkey, David J.
PY - 1997
Y1 - 1997
N2 - Recent work has demonstrated that glucocorticoids, nucleoside analogues, and other cancer chemotherapeutics induce apoptosis in chronic lymphocytic leukemia (CLL) cells. In this study, we investigated the involvement of protease activation in these responses using selective peptide inhibitors of the interleukin-1β converting enzyme (ICE)/caspase family and a Ca2+- activated protease we recently implicated in thymocyte apoptosis. Apoptosis was associated with proteolyric cleavage of poly(adenosine diphosphate [ADP]- ribose) polymerase (PARP) and increased caspase protease activity, and cell- permeant caspase antagonists [zVAD(OMe)fmk and Boc-D(OBzl)cmk] blocked apoptosis in response to the glucocorticoid methylprednisolone or the nucleoside analogue fludarabine, indicating that caspase activation was required for these responses. However, a peptide-based inhibitor of the Ca2+-dependent lamin protease (zAPFcmk) also completely suppressed DNA fragmentation and the cleavage of lamin B1. Strikingly, treatment of cells with zAPFcmk alone led to characteristic PARP cleavage, depletion of the precursor forms of two ICE family proteases (CPP32 and ICH-1), and phosphatidylserine exposure, suggesting that blockade of the lamin protease led to activation of the ICE family. Our results implicate the lamin protease as a target for Ca2+ during chemotherapy-induced apoptosis in CLL lymphocytes, and they identify a novel functional interaction between the protease and members of the ICE family.
AB - Recent work has demonstrated that glucocorticoids, nucleoside analogues, and other cancer chemotherapeutics induce apoptosis in chronic lymphocytic leukemia (CLL) cells. In this study, we investigated the involvement of protease activation in these responses using selective peptide inhibitors of the interleukin-1β converting enzyme (ICE)/caspase family and a Ca2+- activated protease we recently implicated in thymocyte apoptosis. Apoptosis was associated with proteolyric cleavage of poly(adenosine diphosphate [ADP]- ribose) polymerase (PARP) and increased caspase protease activity, and cell- permeant caspase antagonists [zVAD(OMe)fmk and Boc-D(OBzl)cmk] blocked apoptosis in response to the glucocorticoid methylprednisolone or the nucleoside analogue fludarabine, indicating that caspase activation was required for these responses. However, a peptide-based inhibitor of the Ca2+-dependent lamin protease (zAPFcmk) also completely suppressed DNA fragmentation and the cleavage of lamin B1. Strikingly, treatment of cells with zAPFcmk alone led to characteristic PARP cleavage, depletion of the precursor forms of two ICE family proteases (CPP32 and ICH-1), and phosphatidylserine exposure, suggesting that blockade of the lamin protease led to activation of the ICE family. Our results implicate the lamin protease as a target for Ca2+ during chemotherapy-induced apoptosis in CLL lymphocytes, and they identify a novel functional interaction between the protease and members of the ICE family.
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U2 - 10.1182/blood.v90.9.3673
DO - 10.1182/blood.v90.9.3673
M3 - Article
C2 - 9345052
AN - SCOPUS:0030826045
SN - 0006-4971
VL - 90
SP - 3673
EP - 3681
JO - Blood
JF - Blood
IS - 9
ER -