Mitogenic growth signalling, DNA replication licensing, and survival are linked in prostate cancer

Abstract

Activation of mitogen/extracellular-signal-regulated kinase kinase 5/extracellular signal-regulated kinase-5 (MEK5/ERK5) growth signalling is coupled to increased cell proliferation in prostate cancer (PCa). Dysregulation of the DNA replication licensing pathway, a critical step in growth control downstream of transduction signalling pathways, is associated with development of PCa. In this study we have investigated linkages between the MEK5/ERK5 pathway and DNA replication licensing during prostate carcinogenesis. The effects of increased MEK5/ERK5 signalling on the expression of replication licensing factors Mcm2 and geminin and the proliferation marker Ki67 were studied in an ecdysone-inducible system expressing a constitutively activated mutant of MEK5 in EcR293 cells and in stable ERK5 over-expressing PC3 clones. In parallel, expression of these biomarkers in PCa biopsy specimens (n ¼ 58) was studied and compared to clinicopathological parameters. In both in vitro systems induction of MEK5 expression resulted in increased levels of phosphorylated ERK5 and Mcm2, geminin and Ki67 proteins. In PCa specimens average Mcm2 expression was greater than Ki67 and geminin expression (median labelling index (LI) 36.7, 18.1, and 3.4% respectively), consistent with their differential expression according to growth status (Po0.0001). Mcm2, geminin and Ki67 expression were significantly associated with Gleason grade (P ¼ 0.0002, P ¼ 0.0003, P ¼ 0.004); however there was no link with T or M stage. There was a significant relationship between increasing ERK5 expression and increasing Mcm2 (P ¼ 0.003) and Ki67 (P ¼ 0.009) expression, with non-significant trends seen with increasing MEK5 expression. There were significant associations between Gleason grade and the number of cells traversing G1 phase (Ki67 LI -geminin LI ; (P ¼ 0.001)), with high ERK5 levels associated with both an increase in replication licensed but non-cycling cells (Mcm2 LI -Ki67 LI ; (P ¼ 0.01)) and accelerated cell cycle progression (geminin LI /Ki67 LI ; (P ¼ 0.005)), all indicative of a shift towards increasing proliferative potential. While Mcm2 and Ki67 were both prognostic factors on univariate analysis, only Mcm2 remained an independent prognostic marker on multivariate analysis. Taken together, our data show that induction of MEK5/ERK5 signalling is linked to activation of the DNA replication licensing pathway in PCa, and that the strong prognostic value of MCM proteins may result from their function as relay stations coupling growth regulatory pathways to genome duplication.

Aberrant expression of extracellular signal-regulated kinase 5 in human prostate cancer

“…Given the mitotic effect of MEK5/ERK5 signaling in CaP, we explored its link with DNA replication licensing factors using a combination of clinical samples and in vitro cell model (Dudderidge et al, 2007). Significant associations between Gleason grade and the number of cells traversing G 1 phase was observed (P ¼ 0.001), with high ERK5 levels associated with both an increase in replication licensed but noncycling cells (Mcm2 þ ve/Ki67Àve; P ¼ 0.01) and accelerated cell cycle progression (shortened G 1 phase; P ¼ 0.005), phenotype consistent with increasing proliferative potential.…”

Minichromosome maintenance proteins 2, 3 and 7 in medulloblastoma: overexpression and involvement in regulation of cell migration and invasion

“…These cells are competent to reenter the cell division cycle and reside in a G1 extended or arrested state (Todorov et al, 1994;Endl et al, 2001;Stoeber et al, 2001;Williams and Stoeber, 2007). It was shown that increase of this cell population was significantly associated with high tumor grades in renal cell carcinoma, prostate cancer and oligodendroglioma (Dudderidge et al, 2005(Dudderidge et al, , 2007Wharton et al, 2007) and with tumor metastasis in colorectal cancer (Nishihara et al, 2008). We also observed higher labeling indexes for MCM2, MCM3 and MCM7 than that for Ki67 in MB, indicating the presence of this licensed but nonproliferative MB cell population.…”

Mitogen/Extracellular Signal-Regulated Kinase Kinase-5 Promoter Region Polymorphisms Affect the Risk of Sporadic Colorectal Cancer in a Southern Chinese Population

“…Upon activation, the MAPKs selectively phosphorylate cellular targets, leading to regulation of gene expression and biologic events such as proliferation, differentiation, and apoptosis (Ghosh et al, 2005). There are reports that demonstrate that the MEK5/ ERK5 pathway was involved in tumorgenesis and malignancies (Mehta et al, 2003;Dudderidge et al, 2007;Li et al, 2008). Dudderidge et al (2007) showed that the induction of …”

“…There are reports that demonstrate that the MEK5/ ERK5 pathway was involved in tumorgenesis and malignancies (Mehta et al, 2003;Dudderidge et al, 2007;Li et al, 2008). Dudderidge et al (2007) showed that the induction of …”