Protease activation is required for glucocorticoid-induced apoptosis in chronic lymphocytic leukemic lymphocytes

Joya Chandra, Joyce Gilbreath, Emil J. Freireich, Kay Oliver Kliche, Michael Andreeff, Michael Keating, David J. McConkey

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3673-3681
Number of pages9
JournalBlood
Volume90
Issue number9
DOIs
StatePublished - 1997

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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