Aberrant MEK5/ERK5 signalling contributes to human colon cancer progression via NF-κB activation

Aes Simões, D. M. Pereira, S. E. Gomes, H. Brito, T. Carvalho, A. French, R. E. Castro, C. J. Steer, S. N. Thibodeau, C. M.P. Rodrigues, P. M. Borralho

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30 Scopus citations

Abstract

This study was designed to evaluate MEK5 and ERK5 expression in colon cancer progression and to ascertain the relevance of MEK5/ERK5 signalling in colon cancer. Expression of MEK5 and ERK5 was evaluated in 323 human colon cancer samples. To evaluate the role of MEK5/ERK5 signalling in colon cancer, we developed a stable cell line model with differential MEK5/ERK5 activation. Impact of differential MEK5/ERK5 signalling was evaluated on cell cycle progression by flow cytometry and cell migration was evaluated by wound healing and transwell migration assays. Finally, we used an orthotopic xenograft mouse model of colon cancer to assess tumour growth and progression. Our results demonstrated that MEK5 and ERK5 are overexpressed in human adenomas (P<0.01) and adenocarcinomas (P<0.05), where increased ERK5 expression correlated with the acquisition of more invasive and metastatic potential (P<0.05). Interestingly, we observed a significant correlation between ERK5 expression and NF-κB activation in human adenocarcinomas (P<0.001). We also showed that ERK5 overactivation significantly accelerated cell cycle progression (P<0.05) and increased cell migration (P<0.01). Furthermore, cells with overactivated ERK5 displayed increased NF-κB nuclear translocation and transcriptional activity (P<0.05), together with increased expression of the mesenchymal marker vimentin (P<0.05). We further demonstrated that increased NF-κB activation was associated with increased IκB phosphorylation and degradation (P<0.05). Finally, in the mouse model, lymph node metastasis was exclusively seen in orthotopically implanted tumours with overactivated MEK5/ERK5, and not in tumours with inhibited MEK5/ERK5. Our results suggested that MEK5/ERK5/NF-κB signalling pathway is important for tumour onset, progression and metastasis, possibly representing a novel relevant therapeutic target in colon cancer treatment.

Original languageEnglish (US)
Article numbere1718
JournalCell Death and Disease
Volume6
Issue number4
DOIs
StatePublished - Apr 9 2015

Bibliographical note

Funding Information:
Acknowledgements. We thank Dr Robert C Doebele, University of Colorado, CO, USA, for the kind gift of pWPI-GFP lentiviral expression constructs encoding constitutively active MEK5 (pWPI-MEK5DD), dominant-negative MEK5 (pWPI-MEK5AA) and empty vector control (pWPI). We are very thankful to Dr Marta Caridade for assistance with animal experimentation. This study was supported by Fundação para a Ciência e Tecnologia (HMSP-ICT/0018/2011, SFRH/BD/96517-/2013, SFRH/BD/88619/2012 and SFRH/BD/79356/2011).

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