Opposite effect of ERK1/2 and JNK on p53-independent p21 WAF1/CIP1 activation involved in the arsenic trioxide-induced human epidermoid carcinoma A431 cellular cytotoxicity

Huei Sheng Huang, Zi Miao Liu, Ling Ding, Wen Chang Chang, Pei Yin Hsu, Shu Hui Wang, Ching Chi Chi, Cheng Hsin Chuang

研究成果: 雜誌貢獻文章同行評審

23 引文 斯高帕斯(Scopus)

摘要

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 p21 WAF1/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 As 2O3-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.

原文英語
頁(從 - 到)113-125
頁數13
期刊Journal of Biomedical Science
13
發行號1
DOIs
出版狀態已發佈 - 一月 2006

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Pharmacology (medical)

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