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New York University School of Medicine

Superfund Research Program

Molecular Mechanisms of Co-Carcinogenic Effect of Arsenite with UV Radiation (ARRA Funded)

Project Leader: Chuanshu Huang
Grant Number: P42ES010344
Funding Period: 2009-2011

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Project Summary (2009-2011)

Although arsenic is acknowledged to be a co-carcinogen with ultraviolet (UV) radiation for skin tumor induction in mice, its action at the cellular and molecular level is not yet understood. Preliminary data shows that arsenite inhibits UV-induced cell apoptosis in mouse epidermal CI41 cells. The data also demonstrates that arsenite induces COX-2 expression, and activation of phosphatidylinositol 3-kinase (PI-3K) and Akt in CI41 cells and the nuclear factor kB (NFkB) both in vitro and in vivo, and has a synergistic effect with DVB on NFkB activation in CI41 cells. Considering the important role of PI-3K/Akt, NFkB and COX-2 in the protection of cells from apoptosis, the main hypothesis of this research is that activation of Pl-3K/Akt, NFkB and/or induction of COX-2, plays an essential role in the arsenite protection of mouse skin cells from UV- induced apoptosis. Dr. Huang will use specific gene knockout, gene knockdown, and other molecular and cellular approaches to test this novel hypothesis in accordance with the following specific aims:

  1. To identify signaling pathways implicated in arsenite protection of mouse skin cells from UV-induced cell apoptosis in vitro.
  2. To elucidate downstream genes involved in the arsenite antagonizing apoptosis caused by UVB radiation in mouse cell culture models.
  3. To determine the effect of arsenite on UV-induced activation of Akt, NFkB, and COX-2 expression in vivo.
  4. To test whether arsenite is able to inhibit UV-induced apoptosis and whether NFkB activation is required for this inhibition in vivo.

The significance of this application includes:

  1. Suppression of apoptosis by arsenite may be an important mechanism by which arsenite acts as a co-carcinogen. It may facilitate skin cancer development by supporting the survival of the cells with genetic alterations induced by UV radiation, which is usually eliminated by apoptosis.
  2. The understanding of the molecular mechanisms of co-carcinogenesis of arsenite with UV radiation in mouse skin will help to understand cancer development caused by arsenite in human skin.
  3. A better understanding of molecular mechanisms of cancer development caused by arsenite in vitro and in vivo will provide valuable information to help design more effective agents for prevention of cancers caused by arsenite.


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