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

Nature Communications
H Y ChowJonathan Chernoff

Abstract

p21-activated kinases (Paks) play an important role in oncogenic signaling pathways and have been considered as potential therapeutic targets in various cancers. Most studies of Pak function employ gene knock-out or knock-down methods, but these approaches result in loss of both enzymatic and scaffolding properties of these proteins, and thus may not reflect the effects of small molecule inhibitors. Here we use a transgenic mouse model in which a specific peptide inhibitor of Group I Paks is conditionally expressed in response to Cre recombinase. Using this model, we show that inhibition of endogenous Paks 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 β-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.

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Citations

Mar 18, 2020·Cancers·Larissa Kotelevets, Eric Chastre
Jul 2, 2020·Endocrinology·Luis BautistaMatthew D Ringel
Jul 18, 2020·Biochimica Et Biophysica Acta. General Subjects·Reem EldawudCerasela Zoica Dinu
Nov 24, 2021·Biological Reviews of the Cambridge Philosophical Society·Yan Wang, Fuzheng Guo
Dec 18, 2021·Science Advances·Aishwarya SubramanianW Brent Derry

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Methods Mentioned

BETA
GTPases
gene knockdown
gene knock out
GTPase
transgenic
PCR
biopsies
biopsy
xenografts
xenograft

Software Mentioned

cummeRbund
CuffDiff
Samtools
SAM
Image J
Bowtie2
TopHat
CutAdapt
FastQC

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