IGF‐I and EGF promote synergistic increases in proliferation, enhances IGF‐IR activation and increases nuclear β‐catenin in intestinal epithelial cells

Abstract

Insulin‐like growth factor I (IGF‐I) and epidermal growth factor (EGF) increase risk and promote pathogenesis of colon cancer in humans. Studies suggest that these pathways may interact to promote synergistic effects on colon cancer cells. We tested the hypothesis that combined IGF‐I and EGF treatment will additively or synergistically increase proliferation of intestinal epithelial cells and activate tumor‐promoting pathways, such as the β‐catenin pathway. IEC‐6 cells, a non‐transformed intestinal epithelial cell line, were treated with IGF‐I and EGF, alone or in combination. DNA synthesis was assayed using H3‐thymidine. EGF stimulated DNA synthesis more potently than IGF‐I, but combined IGF and EGF treatment synergistically increased DNA synthesis. EGF pretreatment, followed by IGF‐I treatment increased IGF‐IR tyrosine phosphorylation. EGF alone increased total IGF‐IR and this was enhanced by EGF pretreatment and subsequent IGF‐I treatment. EGF increased nuclear β‐catenin and synergistically enhanced IGF‐I‐induced nuclear β‐catenin. Ongoing studies will determine whether inhibition of both IGF‐IR and EGFR signaling decreases tumorigenesis, in vivo. These studies suggest that interactions between IGF‐I and EGF may reduce the effectiveness of anti‐cancer therapies that specifically target these pathways in colon cancer. [NIH‐DK40274‐16 RO1 and NIH‐DK44769‐10 CCFA].