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Retinoid‐induced apoptosis in B‐cell chronic lymphocytic leukaemia cells is mediated through caspase‐3 activation and is independent of p53, the retinoic acid receptor, and differentiation
Author(s) -
Pepper Chris,
Ali Khalida,
Thomas Alun,
Hoy Terry,
Fegan Chris,
Chowdary Pratima,
Kell Jonathan,
Bentley Paul
Publication year - 2002
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1034/j.1600-0609.2002.02799.x
Subject(s) - apoptosis , retinoic acid , programmed cell death , retinoic acid receptor , tretinoin , caspase , microbiology and biotechnology , biology , cancer research , retinoid , cellular differentiation , retinoic acid receptor alpha , caspase 3 , cell culture , biochemistry , gene , genetics
The aim of this study was to investigate the effects of all‐ trans retinoic acid (ATRA) on apoptosis induction, Bcl‐2 family protein expression, and differentiation in B‐cell chronic lymphocytic leukaemia (B‐CLL) cells. ATRA induced apoptosis in all the B‐CLL samples tested, and this was accompanied by a specific reduction in Bcl‐2 and Mcl‐1 protein expression in the apoptotic cells. In contrast, Bax, p21, and p53 expression was not altered in either the viable or apoptotic B‐CLL cells, inferring that ATRA utilises a p53‐independent cell death pathway. Caspase‐3 activation was shown to be a prerequisite for ATRA‐induced apoptosis, which was inhibited by the pan‐caspase inhibitor Z‐VAD‐FMK and the caspase‐9 inhibitor Z‐LEHD‐FMK. In addition, the retinoic acid receptor (RAR) antagonist AGN194310 failed to abrogate the apoptotic effects of ATRA, indicating that RAR binding was not necessary for ATRA‐induced apoptosis. Furthermore, there was no evidence of ATRA‐induced differentiation of the B‐CLL cells in this study either in terms of altered morphology or immunophenotype. In summary these data indicate that ATRA induces apoptosis via the intrinsic apoptotic pathway, and this is independent of RAR binding, p53 activation, and cellular differentiation in B‐CLL cells.