Abstract 3125: Upregulation of gap junctions with substituted quinolines in colon cancer cells

Abstract

Abstract Colon cancer is one of the most common cancers in the United States with a high predisposition to metastasize. Furthermore, 30-40% of patients have metastatic disease at the initial diagnosis. Cancer cells exhibit many deficiencies in cell-to-cell communication, particularly gap junctional intercellular communication (GJIC). GJIC has been reported to diminish as cancer cells progress. Gap junctions are intercellular channels composed of connexin proteins, which mediate the direct passage of small molecules from one cell to the next. They are involved in the regulation of cell cycle, cell differentiation, and cell signaling. Previous work demonstrated that connexin proteins such as Cx43, Cx32 and Cx26 have a distinct pattern in SW480, SW620, HT29 and Caco-2 human colon cancer cell lines. The findings suggest that the lack of GJIC, in part due to low level of connexin, may contribute to facilitate colon cancer progression. Since the regulation of gap junction is lost in colon cancer cells, the goal of this study is to restore GJIC in colon cancer cells. Recently, substituted quinolines (PQs), gap junction enhancers, have been shown to increase gap junction activity in breast cancer cells. The level of Cx43 is low in SW620 and SW480 human colon cancer cells. Transfected Cx43 cells have a 6-fold increase of gap junction activity compared to control using scrape load/dye transfer assay. Western blot analysis confirmed that a significant level of Cx43 was expressed in transfected Cx43 cells compared to control. This suggests that overexpressing Cx43 can restore GJIC. Interestingly, 200 nM PQ1 causes a 4-fold increase of gap junction activity as well and subsequently causes a decrease in cell proliferation by 15%. However, TPA, GJIC inhibitor, can reverse the gap junction activity of transfected Cx43 or treated PQ1 cells. Further analysis of Cx43, survivin, and cyclin D1 in treated cells was observed. Overall, the results show that substituted quinolines can directly enhance gap junction activity and attenuate cell proliferation in colon cancer cells. The findings provide an important implication in which restoration of gap junction activity can be targeted for drug development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3125. doi:10.1158/1538-7445.AM2011-3125