pf-3758309 and Cell-Transformation--Neoplastic

P21-activated kinase 1 (PAK1) stimulates growth and metastasis of colorectal cancer (CRC) through activation of multiple signalling pathways. Up-regulation of CRC stem cell markers by PAK1 also contributes to the resistance of CRC to 5-fluorouracil. The aim of this study was to investigate the effect of PAK1 depletion and inhibition on the immune system and on intestinal tumour formation in APC. The PAK1 KO APC. Compared to APC. Depletion of active PAK1 up-regulates the immune system of APC

Topics: Animals; Biomarkers; Cell Line, Tumor; Cell Transformation, Neoplastic; Colorectal Neoplasms; Disease Models, Animal; Genes, APC; Genotype; Immune System; Immunohistochemistry; Immunomodulation; Leukocyte Count; Lymphocytes; Mice; Mice, Knockout; Neutrophils; p21-Activated Kinases; Polycomb Repressive Complex 1; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Pyrazoles; Pyrroles

p21-Activated kinase-1 (Pak1) is frequently upregulated in human breast cancer and is required for transformation of mammary epithelial cells by ErbB2. Here, we show that loss of Pak1, but not the closely related Pak2, leads to diminished expression of β-catenin and its target genes. In MMTV-ErbB2 transgenic mice, loss of Pak1 prolonged survival, and mammary tissues of such mice showed loss of β-catenin. Expression of a β-catenin mutant bearing a phospho-mimetic mutation at Ser 675, a specific Pak1 phosphorylation site, restored transformation to ErbB2-positive, Pak1-deficient mammary epithelial cells. Mice bearing xenografts of ErbB2-positive breast cancer cells showed tumor regression when treated with small-molecule inhibitors of Pak or β-catenin, and combined inhibition by both agents was synergistic. These data delineate a signaling pathway from ErbB2 to Pak to β-catenin that is required for efficient transformation of mammary epithelial cells, and suggest new therapeutic strategies in ErbB2-positive breast cancer.

Topics: Animals; Apoptosis; beta Catenin; Blotting, Western; Breast Neoplasms; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Dose-Response Relationship, Drug; Epithelial Cells; Humans; Mice; Mice, Inbred ICR; Mice, Knockout; Mice, SCID; Mice, Transgenic; p21-Activated Kinases; Pyrazoles; Pyrroles; Receptor, ErbB-2; RNA Interference; Xenograft Model Antitumor Assays