P21‐activated kinase 5 is overexpressed during colorectal cancer progression and regulates colorectal carcinoma cell adhesion and migration

Abstract

P21-activated kinase 5 (PAK5) is the recently identified member of the group B p21-activated kinase (PAK) family which are effectors of the small GTPase Cdc42 and Rac1, known to regulate cell motility and activate cell-survival signaling pathways. However, overexpression of PAK5 has not been associated with any cancers so far. Interestingly, we found that PAK5 was overexpressed in a variety of colorectal carcinoma (CRC) cell lines in a Western-blotting examination. Therefore, in this study, we aim to examine the PAK5 expression during CRC progression and to answer if PAK5 is involved in malignant progression of CRC. By immunohistochemistry, our results showed that PAK5 expression was increased with CRC progression through the adenoma to carcinoma sequence, with the most significant increases in invasive and metastatic CRCs (p < 0.0001). Furthermore, increased PAK5 expression was also found with the development of CRC from lower Duke's grades to higher ones (p < 0.01). Moreover, PAK5 was also increased from well to poorly differentiated CRCs (p < 0.01). Using gain and loss of function experiments, we found that PAK5 reduced CRC cell adhesion but promoted their migration on collagen type I. Taken together, our study demonstrated that PAK5 expression increased significantly with malignant progression of CRC and that PAK5 might promote CRC metastasis by regulating CRC cell adhesion and migration. ' UICCKey words: colorectal carcinoma; PAK5; cancer cell adhesion and migration P21-activated kinases (PAKs), a family of serine/threonine kinases, are small GTPase effectors that play important roles in regulating cell shape, movement, proliferation and survival. [1][2][3] PAKs are characterized by a highly conserved amino-terminal Cdc42/ Rac interactive binding (CRIB) domain and a carboxyl terminal kinase domain. [4][5][6] Six human PAKs were identified and divided into two groups based on their amino acid sequences and their functions. Group A PAKs (PAK1, 2 and 3) share 80 to 90% sequence identity within their catalytic domains, whereas the recently identified group B PAKs (PAK4, 5 and 6), show only approximately 50% identity to the kinase domains of the group A PAKs. 6,7 A marked difference between the two PAK groups is the autologous inhibitory sequence in the NH2-terminal regulatory domain found in group A PAKs, with no obvious homologous sequence in group B. 7 Unlike group A PAKs, whose binding of Cdc42 and Rac leads to their activation, Group B PAKs are not strongly activated by GTPase binding. 8 Of the three group B PAKs, PAK4 was the best characterized, involving in cell adhesion, migration, proliferation and activation of cell-survival pathways that lead to protection from apoptosis. 9,10 Our previous study demonstrated that PAK4 regulated integrin avb5-mediated breast carcinoma cell migration. 11 Different PAK family members have different tissue-specific expression patterns. PAK4 was found to be overexpressed in 78% of a variety of human cancer cell lines, 12 whereas PAK5 and PAK6 showed restricted tissue-spe...

PAK5 mediates cell: cell adhesion integrity via interaction with E-cadherin in bladder cancer cells

“…Moreover we find differential levels of PAK5 mRNA expression in human normal bladder tissue compared to carcinoma samples. Our findings are not in agreement with some previous reports that suggest PAK5 expression increases with malignant disease in colorectal 60,61 , gastric 62 and hepatocellular carcinoma 63 . However, on reviewing these publications, the sensitivity and specificity antibodies used to detect PAK5…”

“…For example in the colorectal study 61 , the isoform specificity of the polyclonal antibody has not been well described. The epitope for antibody recognition was generated against 224-amino acids N-terminal sequence of PAK5, and cross reaction with PAK4 was excluded.…”

P21-activated kinase 5 plays essential roles in the proliferation and tumorigenicity of human hepatocellular carcinoma

“…PAK4 is closely associated with the progression and metastasis of breast cancer [32] , the adhesion of prostate cancer cells [33] and the migration of human gastric cancer cells [34] , and PAK6 is overexpressed in prostate cancer and breast cancer cell lines [29,35] . Several studies have provided detailed insights into the role of the PAK5 protein in colorectal cancer [15,16] and pancreatic [17] . However, the role of PAK5 in HCC tumorigenesis remains poorly understood.…”

“…The other members of the PAK family have been identified as regulators of tumor formation in the breast [10] , colon [11] , ovary [12] , pancreas [13] , and prostate [14] . Although the role of PAK5 in cancer progression has not been fully investigated, two recent reports suggest that PAK5 is overexpressed in colorectal cancer and can promote cancer-cell invasion [15,16] . Furthermore, the combined inhibition of PAK7, MAP3K7, and CK2a kinases was shown to inhibit the growth of MiaPaCa2 pancreatic cancer cell xenografts [17] .…”

High expression of P21-activated kinase 5 protein is associated with poor survival in gastric cancer

“…The role of PAK5 in various types of cancer has been investigated by several groups. Inhibiting PAK5 expression induced a 7-fold increase in apoptosis in the pancreatic adenocarcinoma cell line MiaPaCa-2, suggesting that PAK5 is a kinase that may protect pancreatic cancer cells from apoptosis (11) PAK5 overexpression assessed using immunohistochemistry was reported in certain colorectal cancer types, and PAK5 reduced colorectal carcinoma cell adhesion; however PAK5 promoted cellular migration on collagen type I, indicating that PAK5 is involved in colorectal cancer cell migration and invasion (12). Immunohistochemical analysis demonstrated that PAK5 expression was upregulated significantly in different gastric cancer cell lines and gastric cancer tissue samples, as compared with human embryonic kidney 293 cells and adjacent normal tissue samples (13).…”