Summary
While arsenic trioxide (As2O3) is an infamous carcinogen, it is also an effective chemotherapeutic agent for acute promyelocytic leukemia and some solid tumors. In human epidermoid carcinoma A431 cells, we found that As2O3 induced cell death in time- and dose-dependent manners. Similarly, dependent regulation of the p21WAF1/CIP1 (p21) promoter, mRNA synthesis, and resultant protein expression was also observed. Additionally, transfection of a small interfering RNA of p21 could block the As2O3-induced cell growth arrest. The As2O3-induced p21 activation was attenuated by inhibitors of EGFR and MEK in a dose-dependent manner. Using a reporter assay, we demonstrated the involvement of the EGFR-Ras-Raf-ERK1/2 pathway in the promoter activation. In contrast, JNK inhibitor enhanced the As2O3-induced p21 activation, also in a dose-dependent fashion. Over-expression of a dominant negative JNK plasmid likewise also enhanced this activation. Furthermore, MEK inhibitor attenuated the anti-tumor effect of As2O3. In contrast, in combination with JNK inhibitor and As2O3 enhanced cellular cytotoxicity. Therefore, we conclude that in A431 cells the ERK1/2 and JNK pathways might differentially contribute to As2O3-induced p21 expression and then due to cellular cytotoxicity.
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Acknowledgements
We are greatly indebted to Dr. Bert Vogelstein (Johns Hopkins University Medical Institutions, Baltimore, Maryland, USA) for providing the WWP-luc plasmid. We also thank Dr. Ushio Kikkawa (Kobe University, Kobe, Japan) for his critical review of this manuscript. This work was supported by grants NSC92-2314-B-006-149 and NSC93-2314-B-006-126 from National Science Council of the Republic of China.
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Huang, HS., Liu, ZM., Ding, L. et al. Opposite effect of ERK1/2 and JNK on p53-independent p21WAF1/CIP1 activation involved in the arsenic trioxide-induced human epidermoid carcinoma A431 cellular cytotoxicity. J Biomed Sci 13, 113–125 (2006). https://doi.org/10.1007/s11373-005-9040-z
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DOI: https://doi.org/10.1007/s11373-005-9040-z