Involvement of Activated Cdc42 Kinase1 in Colitis and Colorectal Neoplasms

Abstract

BackgroundActivated Cdc42 kinase1 (ACK1) is a non-receptor tyrosine kinase which is critical for cell survival, proliferation, and migration. Genomic amplification of ACK1 has been reported in multiple human cancers. We aimed to investigate ACK1 protein expression in colorectal mucosa with inflammation and neoplasm, and to evaluate its correlation with disease activity and severity.Material/MethodsA total of 250 individuals who underwent total colonoscopy were collected randomly from January 2007 to May 2013 in Nanfang Hospital, Guangzhou, China. Colorectal mucosal biopsy specimens were obtained by endoscopy from 78 patients with ulcerative colitis (UC), 22 with Crohn’s disease (CD), 20 with infectious colitis, 26 with non-IBD and noninfectious colitis, 16 with sporadic adenomas, 4 with dysplasia-associated lesions or masses, 10 with sporadic colorectal cancer (CRC), 4 with UC-related CRC, 10 with hyperplastic polyps, and 60 without colonic abnormalities. ACK1 protein levels were determined immunohistochemically. The correlations of ACK1 expression with disease activity and severity were also evaluated.ResultsSignificantly increased ACK1 expression was observed in epithelial cells of colorectal mucosa with inflammation and dysplasia compared to controls (P<0.05). ACK1 expression correlated with clinical activity in IBD (χ2=4.57, P=0.033 for UC; χ2=5.68, P=0.017 for CD), as well as grade of dysplasia in preneoplastic lesions (P<0.05). No significant differences in ACK1 expression were found between UC and CD, or between IBD and non-IBD conditions (P>0.05).ConclusionsACK1 protein is increased extensively in colitis and colorectal dysplasia. ACK1 overexpression may play a role in colorectal inflammation and neoplasms.

Small Molecules Targeting Activated Cdc42-Associated Kinase 1 (ACK1/TNK2) for the Treatment of Cancers

“…Moreover, because ACK1 is able to promote cell migration and proliferation, it is presumed that ACK1 may participate in maintaining the integrity of colonic and rectal epithelial barriers in inflammatory diseases. Overall, ACK1 has an impact on the incidence of colorectal inflammation, the mechanism of which still needs to be further studied. , …”

“…ACK1 is a key drug target for metastatic colorectal cancer treatment . ACK1 expression is widely increased in colorectal dysplasia and is continually activated in the process of colorectal cancer development . Among 6 small molecules identified by the connectivity map that may be associated with colorectal cancer inhibition, ACK1 is the common target of three of them (cinchonine, geldanamycin, nadolol).…”

“…As reported, ACK1 is widely upregulated in IBD and many other types of colitis. 38 Its overexpression has potential effects on the IBD remission stage and possibly associates with certain inflammatory mediators directly released by intestinal epithelial cells, such as TNF-α. TNF-α plays a key role in the pathogenesis of inflammatory bowel disease.…”

“…Overall, ACK1 has an impact on the incidence of colorectal inflammation, the mechanism of which still needs to be further studied. 38,39 ACK1 combines with Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) and phosphorylates it at Tyr113, Tyr128, and Tyr145, which allows pSLP-76 to further recruit many other signaling molecules to form multimeric complexes and guarantees the differentiation of the thymus and the function of mature T cells. 40−42 In addition, Thaker et al 40 found that ACK1 could affect the movement of T cells.…”

Rho GTPases as Key Molecular Players within Intestinal Mucosa and GI Diseases

“…In the context of human intestinal inflammation, the expression of CDC42 is decreased in active IBD, and CDC42 has been suggested as a target of MiR-15a for the regulation of epithelial junctions (ZO1 and E-cadherin) in pediatric patients [ 156 ]. In contrast, another study describe the upregulation of ACK1 (Activated CDC42 kinase1) in colitis as well as colorectal dysplasia [ 157 ].…”