Open AccessRequirement for caspase activation in monocytic differentiation of myeloid leukemia cells
Author(s) -
Pramod Pandey,
Atsuko Nakazawa,
Yasumasa Ito,
Rakesh Datta,
Surender Kharbanda,
Donald Küfe
Publication year - 2000
Publication title -
oncogene
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.395
H-Index - 342
eISSN - 1476-5594
pISSN - 0950-9232
DOI - 10.1038/sj.onc.1203751
Subject(s) - biology , cytochrome c , apoptosis , monocytic leukemia , myeloid leukemia , dna fragmentation , caspase , microbiology and biotechnology , programmed cell death , cell culture , thp1 cell line , cancer research , leukemia , biochemistry , immunology , genetics
Human myeloid leukemia cells respond to 12-tetradecanoylphorbol-13-acetate (TPA) and other activators of protein kinase C (PKC) with the induction of terminal monocytic differentiation. The present studies demonstrate that TPA treatment of U-937 leukemia cells is associated with release of mitochondrial cytochrome c, activation of caspase-3 and induction of internucleosomal DNA fragmentation. By contrast, the TUR cell variant, which is deficient in PKCbeta, failed to respond to TPA with release of cytochrome c and induction of the caspase-3 cascade. Moreover, stable overexpression of PKCbeta in TUR cells reconstituted sensitivity to TPA-induced cytochrome c release and activation of caspase-3. The results also demonstrate that treatment of cells with the caspase inhibitor Z-VAD-fmk blocks both TPA-induced apoptosis and monocytic differentiation. Similar results were obtained in U-937 cells stably expressing the CrmA caspase inhibitor. These findings demonstrate that TPA induces cytochrome c release by a PKCbeta-dependent mechanism and that activation of caspase-mediated signaling is required for induction of the differentiated monocytic phenotype.