ERK5 signalling in prostate cancer promotes an invasive phenotype

Abstract

Background:Aberrant mitogen/extracellular signal-regulated kinase 5 (MEK5)–extracellular signal-regulated protein kinase 5 (ERK5)-mediated signalling has been implicated in a number of tumour types including prostate cancer (PCa). The molecular basis of ERK5-driven carcinogenesis and its clinical relevance remain to be fully characterised.Methods:Modulation of ERK5 expression or function in human PCa PC3 and PC3–ERK5 (stably transfected with ERK5) cells was performed using siRNA-mediated knockdown or the MEK inhibitor PD18435 respectively. In vitro significance of ERK5 signalling was assessed by assays for proliferation, motility, invasion and invadopodia. Expression of matrix metalloproteinases/tissue inhibitors of metalloproteases was determined by Q-RT–PCR. Extracellular signal-regulated protein kinase 5 expression in primary and metastatic PCa was examined using immunohistochemistry.Results:Reduction of ERK5 expression or signalling significantly inhibited the motility and invasive capability of PC3 cells. Extracellular signal-regulated protein kinase 5-mediated signalling significantly promoted formation of in vivo metastasis in an orthotopic PCa model (P<0.05). Invadopodia formation was also enhanced by forced ERK5 expression in PC3 cells. Furthermore, in metastatic PCa, nuclear ERK5 immunoreactivity was significantly upregulated when compared with benign prostatic hyperplasia and primary PCa (P=0.013 and P<0.0001, respectively).Conclusion:Our in vitro, in vivo and clinical data support an important role for the MEK5–ERK5 signalling pathway in invasive PCa, which represents a potential target for therapy in primary and metastatic PCa.

Enterolobium contortisiliquum Trypsin Inhibitor (EcTI), a Plant Proteinase Inhibitor, Decreases in Vitro Cell Adhesion and Invasion by Inhibition of Src Protein-Focal Adhesion Kinase (FAK) Signaling Pathways

“…Therefore, inhibition of extracellular proteinases and more importantly inhibition of invadopodium formation may be an attractive approach for cancer therapy (35)(36)(37)(38)(39). Moreover, considering the complex proteinase network, an inhibitor capable of interfering in invadopodium formation may be useful for the study of tumor progression as well as the study of the involvement of invadopodia in this process.…”

Canonical and Kinase Activity-Independent Mechanisms for Extracellular Signal-Regulated Kinase 5 (ERK5) Nuclear Translocation Require Dissociation of Hsp90 from the ERK5-Cdc37 Complex

“…As the ERK5 pathway is critical for cell proliferation, we next tested if overexpressed Cdc37 collaborates with ERK5 to promote cell proliferation. We used human prostate cancer PC-3 cells, since prostatic cells that overexpress MEK5 or EKR5 show an enhanced proliferation rate and enhanced efficiency in forming tumors in vivo (42)(43)(44). PC-3 cells were cotransfected with plasmids encoding GFP or GFP-ERK5, alone or together with those encoding MEK5DD or Cdc37, and GFP-positive cells were counted at different days in a flow cytometer.…”

Crude extract of Euphorbia formosana inhibits the migration and invasion of DU145 human prostate cancer cells: The role of matrix metalloproteinase-2/9 inhibition via the MAPK signaling pathway

“…The molecular mechanics of cancer cell migration Crude extract of Euphorbia formosana inhibits the migration and invasion of DU145 human prostate cancer cells: The role of matrix metalloproteinase-2/9 inhibition via the MAPK signaling pathway has been reported to involve cell cytoskeletal remodeling and focal adhesion dynamics (19,20). Matrix metalloproteinases (MMPs) are important in cell growth, angiogenesis, invasion and metastasis of cancer cells (16,(21)(22)(23). Therapeutic agents that are capable of inhibiting MMPs may be efficacious.…”