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PI-3K/Akt pathway-dependent cyclin D1 expression is responsible for arsenite-induced human keratinocyte

Weiming Ouyang1, Wenjing Luo, Dongyun Zhang

  • 1Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.

Environmental Health Perspectives
|January 17, 2008
PubMed
Abstract

Insights

Arsenite exposure causes human skin cancer by activating the PI-3K/Akt pathway, leading to cyclin D1 expression and cell transformation. This study clarifies a key mechanism in arsenite-induced skin carcinogenesis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Dermatology

Background:

  • Long-term arsenite exposure is linked to human skin cancer.
  • The precise mechanisms driving arsenite-induced skin carcinogenesis are not fully understood.

Purpose of the Study:

  • To investigate the role of the PI-3K/Akt/cyclin D1 pathway in arsenite-induced human keratinocyte transformation.
  • To elucidate the signaling mechanisms underlying arsenite's carcinogenic effects on skin cells.

Main Methods:

  • Soft agar assay to assess arsenite-induced cell transformation.
  • Nude mice xenograft model to evaluate tumor formation.
  • Dominant-negative mutants and siRNA for gene knockdown to explore signaling pathways.

Main Results:

  • Arsenite exposure induced anchorage-independent growth (cell transformation) in HaCat cells, confirmed by tumor formation in nude mice.
  • Arsenite activated PI-3K and Akt, which were crucial for anchorage-independent growth.
  • Cyclin D1 was identified as a key downstream mediator in the PI-3K/Akt-driven cell transformation process.

Conclusions:

  • PI-3K/Akt-mediated cyclin D1 expression is a significant factor in arsenite-induced human skin carcinogenesis.
  • This pathway represents a potential therapeutic target for preventing or treating arsenite-related skin cancers.
Keywords:
AktPI-3Karsenitecyclin D1human keratinocyte

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