PI-3K/Akt Pathway-Dependent Cyclin D1 Expression Is Responsible for Arsenite-Induced Human Keratinocyte Transformation

• Published in: Environmental health perspectives Vol. 116; no. 1; pp. 1 - 6
• Main Authors: Weiming Ouyang, Wenjing Luo, Dongyun Zhang, Jinlong Jian, Qian Ma, Li, Jingxia, Shi, Xianglin, Jingyuan Chen, Gao, Jimin, Huang, Chuanshu
• Format: Journal Article
• Language: English
• Published: United States National Institute of Environmental Health Sciences. National Institutes of Health. Department of Health, Education and Welfare 01.01.2008; National Institute of Environmental Health Sciences
• Subjects: Analysis; Animals; Arsenic compounds; Arsenites; Arsenites - toxicity; Carcinogenesis; Carcinogens, Environmental - toxicity; Cell growth; Cell Line; Cell proliferation; Cell Proliferation - drug effects; Cell transformation; Cell Transformation, Neoplastic; Cultured cells; Cyclin D; Cyclins; Cyclins - genetics; Cyclins - metabolism; Development and progression; Environmental health; Female; Health aspects; Humans; Keratinocytes; Keratinocytes - drug effects; Keratinocytes - metabolism; Keratinocytes - pathology; Mice; Mice, Nude; Neoplasm Transplantation; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Risk factors; RNA, Small Interfering - genetics; Skin cancer; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Small interfering RNA; Transfection; Tumors; cyclin D1; Akt; PI-3K; arsenite; human keratinocyte
• ISSN: 0091-6765; 1552-9924
• DOI: 10.1289/ehp.10403

Background: Long-term exposure of arsenite leads to human skin cancer. However, the exact mechanisms of arsenite-induced human skin carcinogenesis remain to be defined. Objectives: In this study, we investigated the potential role of PI-3K/Akt/cyclin Dlin the transformation of human keratinocytic cells upon arsenite exposure. Methods: We used the soft agar assay to evaluate the cell transformation activity of arsenite exposure and the nude mice xenograft model to determine the tumorigenesis of arsenite-induced transformed cells. We used the dominant negative mutant and gene knockdown approaches to elucidate the signaling pathway involved in this process. Results: Our results showed that repeated long-term exposure of HaCat cells to arsenite caused cell transformation, as indicated by anchorage-independent growth in soft agar. The tumorigenicity of these transformed cells was confirmed in nude mice. Treatment of cells with arsenite also induced significant activation of PI-3K and Akt, which was responsible for the anchorage-independent cell growth induced by arsenite exposure. Furthermore, our data also indicated that cyclin D1 is an important downstream molecule involved in PI-3K/Akt-mediated cell transformation upon arsenite exposure based on the facts that inhibition of cyclin D1 expression by dominant negative mutants of PI-3K, and Akt, or the knockdown of the cyclin D1 expression by its specific siRNA in the HaCat cells resulted in impairing of anchorage-independent growth of HaCat cells induced by arsenite. Conclusion: Our results demonstrate that PI-3K/Akt-mediated cyclin D1 expression is at least one key event implicated in the arsenite human skin carcinogenic effect.