Depletion of p21-activated kinase 1 up-regulates the immune system of APC ∆14/+ mice and inhibits intestinal tumorigenesis

Abstract

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^∆14/+ mice.

Methods

The PAK1 KO APC^∆14/+ mice were generated by cross-breeding of PAK1 KO mice with APC^∆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^∆14/+ mice. Depletion of PAK1 in APC^∆14/+ mice increased the numbers of splenic T- and B- lymphocytes and decreased the numbers of intestinal tumours. Treatment of APC^∆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^∆14/+ mice and suppresses intestinal tumour development. These observations suggest an important role for PAK1 in the immune response to tumours.

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