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.
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.
Huang
Huei-Sheng
HS
Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan. huanghs@mail.ncku.edu.tw
Liu
Zi-Miao
ZM
Ding
Ling
L
Chang
Wen-Chang
WC
Hsu
Pei-Yin
PY
Wang
Shu-Hui
SH
Chi
Ching-Chi
CC
Chuang
Cheng-Hsin
CH
D000970:Antineoplastic Agents / Q000378:metabolism* / Q000633:toxicity; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010087:Oxides / Q000378:metabolism* / Q000633:toxicity; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D000970:Antineoplastic Agents; D001152:Arsenicals; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D010087:Oxides; D034741:RNA, Small Interfering; D066246:ErbB Receptors; D048490:raf Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D018631:ras Proteins; D000077237:Arsenic Trioxide