Abstract 4371: PI3K/Akt/JNK/c-Jun signaling pathway is a mediator for arsenite-induced cyclin D1 expression and cell growth in human bronchial epithelial cells

Abstract

Abstract Arsenite exposure is associated with an increased risk of lung cancers. Although efforts have been made, the precise mechanisms of the arsenite-induced lung carcinogenesis remain enigmatic. Aberrant cyclin D1 expression is an early event in carcinogenesis often accompanies human malignancies in the lung. Our previous study has shown that arsenite was able to induce cyclin D1 expression in human keratinocyte HaCat and mouse epidermal Cl41 cells to promote cell cycle transition, cell proliferation and transformation, which accounts for its ability to induce skin carcinogenesis. However, the role of Cyclin D1 underlying the arsenite-induced human lung carcinogenesis remain elusive. In the present study, arsenite exposure induced the cell cycle transition, resulting in growth promotion of human bronchial epithelial cells. The promoter activity and the expression of cyclin D1 were augmented in response to arsenite treatment. To further evaluate the effect of cyclin D1 in arsenite-induced cell proliferation, a cyclin D1 siRNA construct was stably introduced into Beas-2B cells. The siRNA blocked the induction/expression of cyclin D1. It has been reported that JNKs mediate the cyclin D1 expression in hematopoietic cells. Therefore, we investigated the potential contribution of JNKs to cyclin D1 expression induced by arsenite. Our results strongly suggest that JNK1 is a major kinase responsible for maintaining the basal level of C-Jun phosphorylation, and both JNK1 and JNK2 are critical for arsenite-induced C-Jun phosphorylation. Moreover, using a loss of function mutant Dp85 or DN-Akt, we demonstrated that the PI-3K/Akt pathway was involved in arsenite-induced upregulation of cyclin D1 and cell proliferation. The introduction of Dp85 or DN-Akt into the cells also inhibited JNKs activation as well as c-Jun phosphorylation, while the growth promotion induced by arsenite was significantly inhibited by the PI3K inhibitor Ly294002 and JNK inhibitor, or by over expression of DN-Akt. Overall, our data suggest a signaling pathway of PI-3K/Akt/JNK/c-Jun/cylin D1 signaling in response to arsenite in human bronchial epithelial cells, which leading to the growth promotion. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4371.