Depletion of p21-activated kinase 1 up-regulates the immune system of APCΔ14/+ mice and inhibits intestinal tumorigenesis

Background: 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(Delta 14/+) mice. Methods: The PAK1 KO APC(Delta 14/+) mice were generated by cross-breeding of PAK1 KO mice with APC(Delta 14/+) mice. Splenic lymphocytes were analysed by flow cytometry, and immunohistochemical staining. The numbers of intestinal tumours were counted. Blood cells were also counted. Results: Compared to APC(+/+) mice, the numbers of both T- and B-lymphocytes were reduced in the spleen of APC(Delta 14/+) mice. Depletion of PAK1 in APC(Delta 14/+) mice increased the numbers of splenic T- and B-lymphocytes and decreased the numbers of intestinal tumours. Treatment of APC(Delta 14/+) mice with PF-3758309, a PAK inhibitor reduced the numbers of intestinal tumours and increased the numbers of blood lymphocytes. Conclusion: Depletion of active PAK1 up-regulates the immune system of APC(Delta 14/+) mice and suppresses intestinal tumour development. These observations suggest an important role for PAK1 in the immune response to tumours.