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Low level, long-term inorganic arsenite exposure causes generalized resistance to apoptosis in cultured human keratinocytes: Potential role in skin co-carcinogenesis

  1. Author:
    Pi, J. B.
    He, Y. Y.
    Bortner, C.
    Huang, J. L.
    Liu, J.
    Zhou, T.
    Qu, W.
    North, S. L.
    Kasprzak, K. S.
    Diwan, B. A.
    Chignell, C. F.
    Waalkes, M. P.

  2. Author Address

    NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC USA. NIEHS, Lab Signal Transduct, Res Triangle Pk, NC USA. Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC USA. NCI, Comparat Carcinogenesis Lab, Frederick, MD 21701 USA. NCI, SAIC Frederick, Basic Res Program, Frederick, MD 21701 USA Waalkes, MP, NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, POB 12233,Mail Drop F0-09,111 Alexander Dr, Res Triangle Pk, NC 27709 USA
    1. Year: 2005
    2. Date: AUG 10
  2. Journal: International Journal of Cancer
    1. 116
    2. 1
    3. Pages: 20-26
  4. Type of Article: Article
  1. Abstract:

    Inorganic arsenic is a human carcinogen that targets the skin. Carcinogenesis is a multistep process in which acquired apoptotic resistance is a common event and prior work in non-skin cells shows acquired resistance to apoptosis occurs with chronic arsenite exposure. In the present study, when HaCaT cells, an immortalized, non-tumorigenic human keratinocyte cell line, were continuously exposed to low-level inorganic arsenite (as sodium arsenite; 100 nM) for 28 weeks, the cells acquired a generalized resistance to apoptosis. This included resistance to apoptosis induced by acute high concentrations of arsenite, ultraviolet A (UVA) irradiation, and several chemotherapeutic compounds (cisplatin, etoposide and doxorubicin). These arsenite-tolerant (As-TL) cells showed similar levels of UVA-induced reactive oxygen species (ROS) and oxidative DNA damage when compared to passage match control cells. Because cellular apoptosis is dependent on the balance between proapoptotic and survival pathways, the roles of protein kinase B (PKB), a key antiapoptotic molecule, in this acquired apoptotic resistance were investigated. Stimulation of apoptosis markedly decreased nuclear phosphorylated PKB (P-PKB) levels in control cells, but As-TL cells showed greatly increased stability of nuclear P-PKB. Pretreatment of the As-TL cells with LY294002 or Wortmannin, which specifically inhibit PKB phosphorylation, completely blocked apoptotic resistance in As-TL cells, indicating acquired apoptotic resistance is associated with increased stability of nuclear P-PKB. Because arsenic and UV irradiation are co-carcinogenic in mouse skin, resistance to UV-induced apoptosis in As-TL cells may allow UV-damaged cells to escape normal cell population controls and initiate the carcinogenic cascade. The observation that As-TL cells show no lessening of UV-induced genotoxicity supports this possibility. (c) 2005 Wiley-Liss, Inc

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  2. WOS: 000229766100004

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