Exploring mek5-erk5 signaling in colorectal cancer : A therapeutic target for chemosensitization

Pereira, Diane M.

http://hdl.handle.net/10451/39744

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Autores

Pereira, Diane M.

Orientador(es)

Rodrigues, Cecília M. P., 1968-

Borralho, Pedro Miguel Martinho, 1979-

Resumo(s)

Colorectal cancer remains one of the leading causes of cancer morbidity and mortality in the world. Despite significant advances in early detection and multimodal care, drug resistance, recurrence, and metastasis persist as major challenges in the management of the disease, calling for the identification of alternative targets for therapeutic intervention. Interestingly, in human colorectal adenomas and adenocarcinomas, there is ample evidence that aberrant MEK5-ERK5 expression and/or activation correlates with tumor-node-metastasis stage. As such, the studies presented in this thesis were conducted with the purpose of defining the contribution of ERK5-mediated signaling to the regulation of hallmark traits associated with disease progression, namely tumor cell resistance to 5-fluorouracil (5-FU), the cornerstone of systemic colorectal cancer treatment; and malignant stem cell-like pools, major players in therapy-refractory disease. Using colorectal cancer cell lines as model, we showed that exposure to 5-FU impairs endogenous MEK5-ERK5 signaling, whereas ectopic expression of a constitutively active MEK5 increases resistance to this drug. Conversely, blocking ERK5 in combination with 5-FU results in impaired tumor cell survival and growth in vitro and in subcutaneous xenografts. Further studies established that ERK5 inhibition promotes 5-FU–induced apoptosis in a TP53-wild-type but not a TP53-null background, implying a p53-dependent axis mediating 5-FU sensitization. In parallel, we demonstrated that MEK5-ERK5 phosphorylation levels are increased in three-dimensional sphere cultures enriched for neoplastic stem-like cells. Further, targeting ERK5 suppresses the rates of tumorsphere formation and the expression/activity of representative markers of immature cancer cell fractions, while sensitizing to 5-FU–based chemotherapy. Moreover, downregulation of NF-κB–mediated IL-8 expression might be a crucial event for the impact of ERK5 inhibition on malignant stem-like phenotypes. Finally, analysis of publicly available databases revealed that increased ERK5 expression correlates with shorter overall survival in colorectal cancer patients, reinforcing the clinical relevance of the MEK5-ERK5 axis. Overall, our findings indicate that upregulated MEK5-ERK5 signaling in colorectal carcinoma cells contributes to a shift to an undifferentiated state, whilst providing a route for cancer (stem) cells to escape cytotoxic insults inflicted by classical chemotherapy, therefore encouraging future investigations on the translational potential of ERK5-targeted agents for antineoplastic treatment and chemosensitization.