The phosphatidylinositol‐3 kinase pathway regulates bladder cancer cell invasion

Abstract

Three of the studies described in this section relate to bladder cancer. The first of these concerns the PI‐3 kinase pathway, which has been a topic of interest in cancer in general. The authors from Sacramento suggest that it may regulate cancer cell invasion, and hope that this may lead to translational therapeutic uses.Another study describes the pharmacological characteristics of Ro115‐1240, which is a selective alpha1A/1L adrenoceptor partial agonist, a compound which may have a future in treating stress urinary incontinence.OBJECTIVESTo investigate the role of the phosphatidylinositol (PI)‐3 kinase pathway in the invasion of bladder cancer cell lines, and to assess the activation of this pathway in primary human bladder tumours.MATERIALS AND METHODSHuman bladder cancer cells were treated with pathway specific inhibitors or were transfected with PI‐3 kinase pathway components. The invasion of cultured bladder cancer cells was analysed by an invasion assay. Bladder cancer cells lines and primary human bladder tumours were analysed for pathway activation by western blotting.RESULTSA specific inhibitor of PI‐3 kinase enzyme activity, Ly294002, potently suppressed the invasive properties of three highly invasive bladder tumour cell lines. Restoration of the PTEN gene to invasive UM‐UC‐3 bladder tumour cells or expression of a dominant‐negative version of the PI‐3 kinase target, Akt, also potently inhibited invasion, indicating a central role for the PI‐3 kinase/Akt pathway in this process. In addition, 55% of primary tumours from patients with bladder cancer had markedly high levels of phosphorylated Akt.CONCLUSIONPharmacological or biochemical inhibition of the PI‐3 kinase pathway drastically reduced the invasive capacity of bladder cancer cell lines; over half of primary human bladder tumours had high Akt phosphorylation, suggesting that the aberrant activation of this pathway may contribute to the invasion of a significant subset of bladder cancers.

Dihydrotestosterone upregulates the expression of epidermal growth factor receptor and ERBB2 in androgen receptor-positive bladder cancer cells

“…In our cohort, pAKT positivity showed an inverse association with deep invasion, confirming a recent report demonstrating significantly higher levels of pAKT in non-invasive bladder cancers than in invasive tumors (Schultz et al 2011). However, earlier studies demonstrated similar overexpression of pAKT between non-invasive and invasive bladder tumors yet induction of invasive capacity of cancer cell lines via the PI3K/AKT pathway (Wu et al 2004, Knowles et al 2009). This study also analyzed and compared the prognostic value of respective expression, using Kaplan-Meier survival curves and log-rank test.…”

Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway

“…80,81 LY294002 has shown successful in vitro dose-dependent cell growth inhibition in ovarian cancer 82 and reduced invasion capacity in bladder cancer cell lines. 59 Acutely, it has shown inhibition of Akt1 phosphorylation in bladder cancer cell lines; however, response with chronic exposure depended on PTEN status. 46 Unfortunately, LY294002's dermal toxicity and risk of severe respiratory depression limits its use in the clinical setting.…”

“…One study of only 20 primary UCC samples found a significantly higher presence of P-Akt in 55% of UCC tumor specimens as compared with normal urothelium. 59 Another study evaluated gene expression profiling of 13 upper tract UCC and found that 76.9% had an Akt activation-specific expression signature. 52 A larger study of 251 UCC tissue microarray samples found that P-Akt was selectively expressed in bladder cancer as compared with normal urothelium.…”

Enzastaurin shows preclinical antitumor activity against human transitional cell carcinoma and enhances the activity of gemcitabine

“…PKC-β is expressed in TCC and other PKC-β inhibitors have preclinical antitumor activity (11,12). The phosphatidylinositol 3-kinase/Akt pathway also seems to be a driver of urothelial TCC (13). Additionally, angiogenesis and vascular endothelial growth factor seem to possess key roles in TCC initiation, progression, and invasion (14)(15)(16)(17)(18).…”