Group I Paks are essential for epithelial-mesenchymal transition in an Apc-driven mouse model of colorectal cancer

p21-activated kinases (Paks) play an important role in oncogenic signaling pathways, and have therefore been considered as potential therapeutic targets in various cancers. Most studies of Pak function employ loss of function methods such as gene knock-out or knock-down, but these approaches result in loss of both the enzymatic and scaffolding properties of these proteins, and thus may not reflect the effects of small molecule inhibitors that block catalytic function. In this study we use a new transgenic mouse model in which a specific peptide inhibitor of Group I Paks (Pak1, -2, and -3) is conditionally expressed in response to Cre recombinase. Using this model, we show that inhibition of endogenous Pak function impedes the transition of adenoma to carcinoma in an Apc-driven mouse model of colorectal cancer. These effects are mediated by inhibition of Wnt signaling through reduced ß-catenin activity as well as suppression of an epithelial-mesenchymal transition program mediated by miR-200 and Snai1. These results highlight the potential therapeutic role of Pak1 inhibitors in colorectal cancer and suggest new therapeutic strategies in this disease. Overall design: We generated a targeted transgenic mouse carrying a conditionally activated PID allele at the Rosa26 locus, and showed that expression of this allele effectively inhibited the activity of Group I Paks in vivo. To assess the global molecular effects of Pak inhibition in Apc-null CRC cells, we next explored the effect of repressing Pak activity on transcription. Total RNA was extracted from PID+ and PID- cells and RNA-sequencing was preformed, followed by pathway analysis and qPCR validation for selected mRNAs.

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Chow HY, Dong B, Valencia CA, Zeng CT, Koch JN, Prudnikova TY, Chernoff J