1. Department of Biochemistry and Graduate Institute of Medicine, Kaohsiung, Taiwan
2. ^†Department of Dermatology, Kaohsiung Medical University, Kaohsiung, Taiwan
3. ^*Department of Internal Medicine and Institute of Molecular Medicine, Taipei, Taiwan
4. ^§Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
5. ^‡Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Kaohsiung, Taiwan

Correspondence: Hsin-Su Yu, Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine. No. 7 Chung-Shan South Road, Taipei, Taiwan 100. Email: dermyu@ha.mc.ntu.edu.tw

Received 5 March 2003; Revised 6 June 2003; Accepted 17 September 2003; Published online 5 January 2004.

Abstract

Epidemiologic studies demonstrated that long-term exposure to arsenic induces arsenical skin cancers, including Bowen's disease. Immunohistochemically, Bowen's disease shows proliferating and apoptotic characteristics. The transcription factors nuclear factor-B (NF-B) and activator protein-1 (AP-1) functionally regulate cell proliferation, transformation, and apoptosis. To investigate the mechanism of arsenic-induced apoptosis and related alterations in NF-B and AP-1 activity, we exposed cultured human foreskin keratinocytes to different concentrations of sodium arsenite. At lower concentrations (1 M), arsenic induced keratinocyte proliferation and enhanced both NF-B and AP-1 activity. At higher concentrations (5 M), arsenic induced keratinocyte apoptosis by the Fas/Fas ligand (FasL) pathway. At apoptosis induction concentrations, NF-B activity was not enhanced; however, AP-1 activity was further enhanced. These results indicated that upregulation of NF-B at lower arsenic concentrations was correlated with keratinocyte proliferation. In contrast, higher concentrations of arsenic enhanced AP-1 and induced Fas/FasL-associated apoptosis. The concentration-dependent arsenic effects on transcription factors activity can help to clarify the mechanisms in arsenic-induced proliferation and apoptosis in keratinocytes.