Depletion of p21-activated kinase 1 up-regulates the immune system of APC 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 mice.

METHODS

The PAK1 KO APC mice were generated by cross-breeding of PAK1 KO mice with APC 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 mice. Depletion of PAK1 in APC mice increased the numbers of splenic T- and B- lymphocytes and decreased the numbers of intestinal tumours. Treatment of APC 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 mice and suppresses intestinal tumour development. These observations suggest an important role for PAK1 in the immune response to tumours.