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Inhibition of JNK signaling diminishes early but not late cellular stress‐induced apoptosis
Author(s) -
Krilleke Dominik,
Ucur Esat,
Pulte Dianne,
SchulzeOsthoff Klaus,
Debatin KlausMichael,
Herr Ingrid
Publication year - 2003
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/ijc.11331
Subject(s) - apoptosis , microbiology and biotechnology , biology , intrinsic apoptosis , cytochrome c , jurkat cells , caspase , programmed cell death , dna fragmentation , uvb induced apoptosis , kinase , signal transduction , fas receptor , phosphatidylserine , cancer research , immunology , biochemistry , phospholipid , immune system , t cell , membrane
The human leukemic T‐cell line Jurkat was used to define the role of the cellular stress pathway with its key player kinase JNK in cancer therapy‐induced apoptosis. JNK activity was inhibited by stable transfection with a dominant negative mutant of the upstream kinase JNKK/MKK4 or with the novel, potent and selective JNK1, ‐2 and ‐3 inhibitor SP600125. Inhibition of JNK activity delayed the onset of apoptosis induced by cisplatin, doxorubicin, γ‐irradiation and CD95‐L but did not prevent apoptosis per se . Early events during apoptosis such as induction of CD95‐L, activation of caspase‐8 and exposure of phosphatidylserine on the cell surface were strongly inhibited. Also, at early time points of apoptosis, loss of the mitochondrial membrane potential and release of cytochrome c were markedly impaired. However, late signaling events during apoptosis such as cleavage of PARP and DNA fragmentation apoptosis were only marginally affected. These findings are in accordance with the activity of initiator and effector caspases. Whereas activity of the initiator caspase‐8 was strongly inhibited early and late after induction, an inhibition of caspase‐3 activity was only observed early after induction of apoptosis. We therefore suggest that cellular stress signaling contributes to the initiation of apoptosis, whereas it might be dispensable for the progression of apoptosis. Dysfunction of this pathway under pathological conditions might contribute to therapy resistance of cancer cells. © 2003 Wiley‐Liss, Inc.