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

Abstract

BackgroundP21-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.MethodsThe 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.ResultsCompared 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.ConclusionDepletion 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3432-0) contains supplementary material, which is available to authorized users.

The Anti-Cancer Effects of Frondoside A

“…The major aspect of the biological effects of frondoside A that cannot be readily explained by PAK-1 inhibition are the immunomodulatory effects of the compound [ 28 , 29 , 30 ]. PAK1 appears to act as an immuno-suppressor, and either PAK1 si-RNA or chemical PAK1-inhibition boosts the immune response in mice [ 59 ]. However, the in vitro effects are seen at concentrations that are much lower than those that have either anti-cancer or PAK-1 inhibitory effects and the in vivo effects are seen with very low doses of the compound [ 28 , 29 ].…”

Group I p21-activated kinases in leukemia cell adhesion to fibronectin

“…This might be associated to higher PAK1 content in primary cells (Fig. 2), but also to inhibition of other target(s) as FRAX597 is less specific compared to IPA-3 (50). Interestingly, FRAX597-induced cell death was also fast in MV4-11 cells (Fig.…”

p21-activated kinase signalling in pancreatic cancer: New insights into tumour biology and immune modulation

“…Two of the latest studies have demonstrated that negative stromal TIL patients had larger tumour at a more advanced stage and showed worse overall survival and liver metastasis[ 138 ], and that an increased number of tumour-infiltrated CD8 + lymphocytes were significantly and independently related to improved disease-free survival and overall survival[ 139 ]. Recently, it was reported that pharmacological or genetic depletion of PAK1 up-regulated the immune response to tumours in a colorectal mouse model (APC 14/+ mouse)[ 140 ].Similarly, the role of PAK in regulating the tumour-associated immune response was investigated in an murine orthotopic pancreatic cancer model[ 66 ]. In agreement with the colorectal model, removal of PAK1 by knock-out or inhibition of PAK1 by PF-3758309 not only suppressed tumour growth in vivo , but also stimulated the immune response by increasing the numbers of splenic CD3 + and CD8 + T lymphocytes as well as by promoting tumour-infiltrating CD3 + T lymphocytes.…”