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NSAIDs Inhibit Cell Migration by Disrupting the Cellular Adhesion Signaling Cascade

Treatment with non‐steroidal anti‐inflammatory drugs (NSAIDs) is associated with a wide range of negative side effects including gastrointestinal toxicity. Various mechanisms have been proposed to account for these effects, including promotion of ulceration and erosion by inhibition of cell migration and wound healing. Our lab has previously demonstrated that NSAIDs inhibit expression and activity of calpains resulting in stunted and uncoordinated cell migration, but the downstream effects of suppression of calpain activity/expression are currently unknown. Accordingly, we used a combination of immunoblotting and immunofluorescence in both migrating and non‐migrating IEC‐6 cells to identify total and phosphorylated forms of adhesion signaling proteins, such as vinculin, PAX, FAK, and talin, which are affected by NSAID treatment. Whereas vinculin was unaffected by NSAID treatment in either resting or migrating cells, there was significance suppression of expression of phosphorylated PAX and talin in both cell populations following treatment with indomethacin or NS‐398. Additionally, there was also a significant decrease in expression of phosphorylated FAK with indomethacin, but a significant increase in phosphorylated FAK with NS‐398 treatment. These data suggest that not only do NSAIDs affect calpain activity, as previously reported, but NSAIDs also significantly disrupt the adhesion signaling cascade required for coordinated cell migration. Further, our results also provide a mechanism to explain the apparent retention of rear cellular adhesions observed in NSAID‐treated migrating cells and provide a broad foundation for understanding the precise molecular mechanisms through which NSAIDs disrupt cell migration and wound healing.