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

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)113-125
Number of pages13
JournalJournal of Biomedical Science
Volume13
Issue number1
DOIs
Publication statusPublished - Jan 2006
Externally publishedYes

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Cytotoxicity
Squamous Cell Carcinoma
Chemical activation
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase Kinases
Tumors
Acute Promyelocytic Leukemia
arsenic trioxide
Cell growth
Cell death
Carcinogens
Small Interfering RNA
Transfection
Assays
Neoplasms
Plasmids
Cell Death
Messenger RNA
Growth

Keywords

  • Arsenic trioxide
  • ERK1/2
  • JNK
  • p21

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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

In: Journal of Biomedical Science, Vol. 13, No. 1, 01.2006, p. 113-125.

Research output: Contribution to journalArticle

Huang, Huei Sheng ; Liu, Zi Miao ; Ding, Ling ; Chang, Wen Chang ; Hsu, Pei Yin ; Wang, Shu Hui ; Chi, Ching Chi ; Chuang, Cheng Hsin. / 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. In: Journal of Biomedical Science. 2006 ; Vol. 13, No. 1. pp. 113-125.
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