Activated JNK brings about accelerated apoptosis of Bcl-2-overexpressing C6 glioma cells on treatment with tamoxifen.
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.
Moodbidri
Madhavi S
MS
Neuro-oncology, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai, India.
Shirsat
Neelam V
NV
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D019254:Genes, bcl-2 / Q000187:drug effects* / Q000502:physiology; D005910:Glioma / Q000201:enzymology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051381:Rats; D013629:Tamoxifen / Q000494:pharmacology*
D013629:Tamoxifen; D048031:JNK Mitogen-Activated Protein Kinases