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Activated JNK brings about accelerated apoptosis of Bcl‐2‐overexpressing C6 glioma cells on treatment with tamoxifen
Author(s) -
Moodbidri Madhavi S.,
Shirsat Neelam V.
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02855.x
Subject(s) - apoptosis , tamoxifen , glioma , cancer research , microbiology and biotechnology , chemistry , biology , medicine , cancer , breast cancer , biochemistry
Tamoxifen causes apoptosis of malignant glial cells at a concentration that does not kill normal astrocytes. C6 glioma cells were stably transfected with a vector expressing Bcl‐2 under the control of metallothionin promoter. Low leaky Bcl‐2 expression offered complete protection against tamoxifen‐induced apoptosis. High Bcl‐2 levels, on the other hand, accelerated the apoptosis, with Bcl‐2‐overexpressing clones dying within 48 h of tamoxifen treatment as compared to 6 days for parental C6 cells. Overexpressed Bcl‐2 is localized primarily in mitochondria and to a much lower extent in endoplasmic reticulum (ER). Only a minor fraction of the overexpressed Bcl‐2 gets phosphorylated in tamoxifen‐treated cells and the phosphorylation does not affect its binding to Bax. Tamoxifen treatment of Bcl‐2‐overexpressing clones was found to result in activation of c‐Jun N‐terminal kinase (JNK) and p38 kinase. Inhibition of JNK but not p38 kinase completely abrogated the accelerated apoptosis. Constitutively expressed endogenous c‐Jun was found to be phosphorylated, resulting in increased activator protein 1 (AP‐1) DNA‐binding activity. Expression of Fas ligand (FasL), an AP‐1 transcriptional target, increased during accelerated cell death. This presumably brought about activation of caspase 8, as inhibition of caspase 8 blocked the apoptosis. The JNK/c‐Jun/AP‐1/FasL pathway could be considered as a potential target for the therapy of gliomas.