TY - JOUR
T1 - 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
AU - Huang, Huei Sheng
AU - Liu, Zi Miao
AU - Ding, Ling
AU - Chang, Wen Chang
AU - Hsu, Pei Yin
AU - Wang, Shu Hui
AU - Chi, Ching Chi
AU - Chuang, Cheng Hsin
N1 - Funding Information:
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 Ki-kkawa (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.
PY - 2006/1
Y1 - 2006/1
N2 - 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.
AB - 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.
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U2 - 10.1007/s11373-005-9040-z
DO - 10.1007/s11373-005-9040-z
M3 - Article
C2 - 16283431
AN - SCOPUS:31544434922
SN - 1021-7770
VL - 13
SP - 113
EP - 125
JO - Journal of biomedical science
JF - Journal of biomedical science
IS - 1
ER -
