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Lack of c-Jun activity increases survival to cisplatin
1Instituto de Investigaciones Bioméicas C.S.I.C./U.A.M., Madrid, Spain.
Abstract:
Antineoplasic agents such as cisplatin and adriamycin execute their pharmacological role by triggering apoptosis. We have studied the mechanism of apoptosis induction by cisplatin and adriamycin. Both drugs activated JNK with slow and persistent kinetics. Adriamycin activated caspase-3 before the rise in JNK activity, while the response to cisplatin occurs hours after JNK activation. The increase in JNK activity was necessary for cisplatin-mediated apoptosis but it was dispensable for adriamycin-induced cell death. Cells derived from c-jun knock out mice were more resistant to cisplatin cell death than normal cells, but no difference was observed in response to adriamycin. Activation of JNK and cell death by cisplatin is mediated by the MEKK1/SEK1 cascade, since expression of dominant negative expression vectors of these kinases blocked both processes. p38 was also activated by cisplatin with similar kinetics as JNK. AP-1 complexes were activated by cisplatin including mainly c-jun/ATF-2 heterodimers suggesting that AP-1-dependent transcription partially mediated cisplatin-induced apoptosis.
Insights
Cisplatin and adriamycin induce apoptosis via distinct pathways. Cisplatin requires JNK activation and AP-1 transcription, while adriamycin
Area of Science:
- Molecular Biology
- Cell Biology
- Pharmacology
Background:
- Antineoplastic agents like cisplatin and adriamycin induce programmed cell death (apoptosis).
- Understanding the precise molecular mechanisms of these agents is crucial for cancer therapy.
- Key signaling pathways, including JNK and p38, are implicated in apoptosis.
Purpose of the Study:
- To elucidate and compare the distinct mechanisms of apoptosis induction by cisplatin and adriamycin.
- To investigate the roles of JNK, p38, and AP-1 transcription factors in drug-mediated cell death.
Main Methods:
- Analysis of JNK and caspase-3 activation kinetics following drug treatment.
- Assessment of apoptosis in cells with genetic modifications (e.g., c-jun knockout).
- Utilized dominant-negative expression vectors to block specific kinase cascades (MEKK1/SEK1).
- Studied AP-1 complex composition and transcriptional activity.
Main Results:
- Both cisplatin and adriamycin activated JNK with slow, persistent kinetics.
- Adriamycin induced caspase-3 activation prior to JNK activation; cisplatin's response lagged significantly behind JNK activation.
- JNK activation was essential for cisplatin-induced apoptosis but not for adriamycin-induced cell death.
- Cisplatin-mediated apoptosis and JNK activation were dependent on the MEKK1/SEK1 cascade.
- Cisplatin also activated p38 kinase, and induced AP-1 complexes containing c-jun/ATF-2, suggesting a role for AP-1 dependent transcription.
Conclusions:
- Cisplatin and adriamycin trigger apoptosis through divergent signaling pathways.
- Cisplatin's apoptotic effect is mediated by the MEKK1/SEK1/JNK pathway and AP-1 transcriptional activity.
- Adriamycin-induced cell death occurs independently of JNK activation, suggesting alternative mechanisms.