Premium
Resistance to apoptosis correlates with a highly proliferative phenotype and loss of Fas and CPP32 (caspase‐3) expression in human leukemia cells
Author(s) -
MartinezLorenzo María J.,
Gamen Susana,
Etxeberria Jaime,
Lasierra Pilar,
Larrad Luis,
Piñeiro Andrés,
Anel Alberto,
Naval Javier,
Alava María A.
Publication year - 1998
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19980130)75:3<473::aid-ijc23>3.0.co;2-8
Subject(s) - jurkat cells , apoptosis , biology , leukemia , fas receptor , cell culture , cytotoxic t cell , programmed cell death , cancer research , u937 cell , fas ligand , microbiology and biotechnology , immunology , immune system , t cell , in vitro , biochemistry , genetics
Apoptosis induced by effector cells of the immune system or by cytotoxic drugs is a main mechanism mediating the prevention or elimination of tumoral cells. For instance, the human T‐cell leukemia Jurkat is sensitive to Fas‐induced apoptosis and to activation‐induced cell death (AICD), and the promonocytic leukemia U937 is sensitive to Fas‐ and TNF‐induced apoptosis. In this work, we have analyzed the mechanisms of resistance to physiological or pharmacological apoptosis in human leukemia by generating highly proliferative (hp) sub‐lines derived from Jurkat and U937 cells. These hp sub‐lines were resistant to Fas‐ and TNF‐induced apoptosis, as well as to AICD. This was due to the complete loss of Fas and TNFR surface expression and, in the case of Jurkat‐derived sub‐lines, also of CD3, CD2 and CD59 molecules. The sub‐lines also completely lacked the expression of the apoptotic protease CPP32, present in parental cells. Moreover, these sub‐lines were no longer sensitive to doxorubicin‐induced apoptosis, which was efficiently blocked by the general caspase inhibitor Z‐VAD‐fmk in the parental cell lines. These data suggest a molecular mechanism for the development of resistance of leukemic cells to physiological and pharmacological apoptosis inducers, giving rise to highly proliferative tumoral phenotypes. These results also indicate that Fas and CPP32 could be useful prognostic markers for the progression and/or therapy outcome of human leukemias. Int. J. Cancer 75:473–481, 1998. © 1998 Wiley‐Liss, Inc.