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

Abstract

Urothelial bladder cancer is a major cause of morbidity and mortality worldwide, causing an estimated 150,000 deaths per year. Whilst non-muscle-invasive bladder tumours can be effectively treated, with high survival rates, many tumours recur, and some will progress to muscle-invasive disease with a much poorer long term prognosis. Thus there is a pressing need to understand the molecular transitions occurring within the progression of bladder cancer to an invasive disease. Tumour invasion is often associated with a down regulation of E-cadherin expression concomitant with a suppression of cell: cell junctions and decreased levels of E-cadherin expression have been reported in higher grade urothelial bladder tumours. We find that expression of E-cadherin in a panel of bladder cancer cell lines correlated with the presence of cell: cell junctions and the level of PAK5 expression. Interestingly exogenous PAK5 has recently been described to be associated with cell: cell junctions and we now find that endogenous PAK5 is localised to cell junctions and interacts with an E-cadherin complex. Moreover, depletion of PAK5 expression significantly reduced junctional integrity. These data suggest a role for PAK5 in maintaining junctional stability and we find that in both our own patient samples and a commercially available datasets that PAK5mRNA levels are reduced in human bladder cancer compared to normal controls. Taken together this study proposes that PAK5 expression levels could be used as a novel prognostic marker for bladder cancer progression. PAK5 mediates cell: cell adhesion integrity via interaction with E-cadherin in bladder cancer cells AbstractUrothelial bladder cancer is a major cause of morbidity and mortality worldwide, causing an estimated 150,000 deaths per year. Whilst non-muscle-invasive bladder tumours can be effectively treated, with high survival rates, many tumours recur, and some will progress to muscle-invasive disease with a much poorer long term prognosis. Thus there is a pressing need to understand the molecular transitions occurring within the progression of bladder cancer to an invasive disease. Tumour invasion is often associated with a down regulation of E-cadherin expression concomitant with a suppression of cell: cell junctions and decreased levels of Ecadherin expression have been reported in higher grade urothelial bladder tumours.We find that expression of E-cadherin in a panel of bladder cancer cell lines correlated with the presence of cell: cell junctions and the level of PAK5 expression.Interestingly exogenous PAK5 has recently been described to be associated with cell: cell junctions and we now find that endogenous PAK5 is localised to cell junctions and interacts with an E-cadherin complex. Moreover, depletion of PAK5 expression significantly reduced junctional integrity. These data suggest a role for PAK5 in maintaining junctional stability and we find that in both our own patient samples and a commercially available datasets that PAK5mRNA levels are reduced in human bladder c...

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