ABSTRACT
BACKGROUND: Prostate cancer cell growth is dependent upon androgen receptor (AR) activation, which is regulated by specific kinases. The aim of the current study is to establish if AR phosphorylation by Cdk1 or ERK1/2 is of prognostic significance. METHODS: Scansite 2.0 was utilised to predict which AR sites are phosphorylated by Cdk1 and ERK1/2. Immunohistochemistry for these sites was then performed on 90 hormone-naive prostate cancer specimens. The interaction between Cdk1/ERK1/2 and AR phosphorylation was investigated in vitro using LNCaP cells. RESULTS: Phosphorylation of AR at serine 515 (pAR(S515)) and PSA at diagnosis were independently associated with decreased time to biochemical relapse. Cdk1 and pCdk1(161), but not ERK1/2, correlated with pAR(S515). High expression of pAR(S515) in patients with a PSA at diagnosis of ≤20 ng ml(-1) was associated with shorter time to biochemical relapse (P=0.019). This translated into a reduction in disease-specific survival (10-year survival, 38.1% vs 100%, P<0.001). In vitro studies demonstrated that treatment with Roscovitine (a Cdk inhibitor) caused a reduction in pCdk1(161) expression, pAR(S515)expression and cellular proliferation. CONCLUSION: In prostate cancer patients with PSA at diagnosis of ≤20 ng ml(-1), phosphorylation of AR at serine 515 by Cdk1 may be an independent prognostic marker.
Subject(s)
MAP Kinase Signaling System/physiology , Prostatic Neoplasms/metabolism , Purines/pharmacokinetics , Receptors, Androgen/metabolism , Aged , Biomarkers, Tumor/antagonists & inhibitors , CDC2 Protein Kinase/antagonists & inhibitors , CDC2 Protein Kinase/metabolism , Disease-Free Survival , Humans , Male , Phosphorylation , Prognosis , Prostate-Specific Antigen/metabolism , Recurrence , Roscovitine , Serine/metabolismABSTRACT
BACKGROUND: The aim of this current study was to assess the expression and activity of Src family kinases, focal adhesion kinase (FAK), caveolin (Cav-1) and RhoGD12 in bladder cancer. METHODS: Fifty-eight patients with a new diagnosis of bladder cancer undergoing transurethral resection were included. Immunohistochemical staining was utilised to assess expression of c-Src, dephosphorylated (SrcY(530)), phosphorylated Src (Y(419)), phosphorylated FAK (FAK Y(861)), Cav-1 and RhoGD12. Expression was assessed using the weighted histoscore method. RESULTS: High expression of dephosphorylated Y(527), phosphorylated Y(416) and phosphorylated FAK Y(861) in the membrane were associated with increased cancer-specific survival (P=0. 01, P=0.001, P=0.008, respectively) and expression of Y(416) in the membrane was an independent factor on multivariate analysis when combined with known clinical parameters (P=0.008, HR 0.288, 95% CI 0.11-0.72). CONCLUSION: These results demonstrate that in contrast to other solid tumours, activation of the Src family members and downstream signalling proteins are associated with a good prognosis in transitional cell carcinoma of the bladder, and activated Src has a positive relationship with RhoGD12.
Subject(s)
Carcinoma, Transitional Cell/metabolism , Caveolin 1/metabolism , Guanine Nucleotide Dissociation Inhibitors/metabolism , Protein-Tyrosine Kinases/metabolism , Urinary Bladder Neoplasms/metabolism , CSK Tyrosine-Protein Kinase , Carcinoma, Transitional Cell/mortality , Carcinoma, Transitional Cell/pathology , Caveolin 1/genetics , Cell Membrane/metabolism , Cell Nucleus/metabolism , Cytoplasm/metabolism , Enzyme Activation , Focal Adhesion Protein-Tyrosine Kinases/genetics , Focal Adhesion Protein-Tyrosine Kinases/metabolism , Gene Expression , Guanine Nucleotide Dissociation Inhibitors/genetics , Humans , Kaplan-Meier Estimate , Middle Aged , Multivariate Analysis , Neoplasm Grading , Phosphorylation , Prognosis , Protein-Tyrosine Kinases/genetics , Urinary Bladder Neoplasms/mortality , Urinary Bladder Neoplasms/pathology , rho-Specific Guanine Nucleotide Dissociation Inhibitors , src-Family KinasesABSTRACT
PURPOSE: It has recently been reported that CD4+ T-lymphocytes are reduced in advanced colorectal cancer patients. However, it is not clear whether such changes in T-lymphocyte subsets are an early or late event in such patients. The aim of this study was to examine the relationship between these subsets and disease progression in colorectal cancer. METHODS: Flow cytometric analysis of T-lymphocyte subsets was performed in 39 patients who, approximately 12 months previously, had undergone surgery for colorectal cancer. These patients were grouped according to whether they developed a recurrence in the following two years. A group of healthy subjects was studied as controls. RESULTS: There was a significant increase in the median neutrophil count (4.3 vs. 3.7 10(6)/ml) and the median numbers of platelets (282 vs. 216 10(6)/ml) of the recurrence group compared with the control group, respectively (P < 0.05). The median numbers (0.28 vs. 0.73 10(6)/ml) and percentage (29 vs. 38 percent) of CD4+ T-lymphocytes of the recurrence group were significantly reduced compared with that of the control group (P < 0.05). There were also reductions in the median percentage of CD3+ cells (67 vs. 74 percent) and the median numbers of CD4+ T-lymphocytes (0.28 vs. 0.46 10(6)/ml) of the recurrence group compared with the no recurrence group (P < 0.05). CONCLUSIONS: Reduction of CD4+ T-lymphocytes occurs before detectable recurrence of colorectal cancer. Results of the present study are consistent with impaired immunity, as measured by such lymphocyte subset populations, being important in tumor recurrence in colorectal cancer.
