Sustained activation of JNK/p38 MAPK pathways in response to cisplatin leads to Fas ligand induction and cell death in ovarian carcinoma cells.
The efficacy of cisplatin in cancer chemotherapy is limited by the development of resistance. Although the molecular mechanisms involved in chemoresistance are poorly understood, cellular response to cisplatin is known to involve activation of MAPK and other signal transduction pathways. An understanding of early signal transduction events in the response to cisplatin could be valuable for improving the efficacy of cancer therapy. We compared cisplatin-induced activation of three MAPKs, JNK, p38, and ERK, in a cisplatin-sensitive human ovarian carcinoma cell line (2008) and its resistant subclone (2008C13). The JNK and p38 pathways were activated differentially in response to cisplatin, with the cisplatin-sensitive cells showing prolonged activation (8-12 h) and the cisplatin-resistant cells showing only transient activation (1-3 h) of JNK and p38. In the sensitive cells, inhibition of cisplatin-induced JNK and p38 activation blocked cisplatin-induced apoptosis; persistent activation of JNK resulted in hyperphosphorylation of the c-Jun transcription factor, which in turn stimulated the transcription of an immediate downstream target, the death inducer Fas ligand (FasL). Sequestration of FasL by incubation with a neutralizing anti-FasL antibody inhibited cisplatin-induced apoptosis. In contrast, chemoresistance in 2008C13 cells was associated with failure to up-regulate FasL. Moreover, in these cells, selective stimulation of the JNK/p38 MAPK pathways by adenovirus-mediated delivery of recombinant MKK7 or MKK3 led to sensitization to apoptosis through reactivating FasL expression. Thus, the JNK > c-Jun > FasL > Fas pathway plays an important role in mediating cisplatin-induced apoptosis in ovarian cancer cells, and the duration of JNK activation is critical in determining whether cells survive or undergo apoptosis.
Mansouri
Abdellah
A
Department of Molecular Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030,USA.
Ridgway
Lon D
LD
Korapati
Anita L
AL
Zhang
Qingxiu
Q
Tian
Ling
L
Wang
Yibin
Y
Siddik
Zahid H
ZH
Mills
Gordon B
GB
Claret
François X
FX
D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D053222:Fas Ligand Protein; D005260:Female; D015870:Gene Expression; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011994:Recombinant Proteins; D014162:Transfection; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D016755:Proto-Oncogene Proteins c-jun; D011994:Recombinant Proteins; D011505:Protein-Tyrosine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; C482530:MAP2K3 protein, human; C482569:MAP2K7 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D002945:Cisplatin