Targeting ERK5 in colon cancer stem-like cells

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Targeting ERK5 in colon cancer stem-like cells

Thursday, 09.05.2019

A research team led by Cecília Rodrigues, from the Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, has identified a new molecular pathway underlying the maintenance of stem cell-like features in colon cancer cells. This study was published in Cell Death Discovery. The presence of cancer stem cells within tumors, including those from the colon and rectum, is associated with increased therapy resistance and worse clinical outcomes. This provided the rationale for several undergoing clinical trials assessing the efficacy of specifically targeting this undifferentiated malignant state along with current anticancer regimens. In this study, the authors establish proof of principle that pharmacological inhibition of the MEK5-ERK5 pathway, commonly upregulated in colorectal tumors, may be an effective strategy to target self-renewing, drug-resistant cancer stem-like cells, encouraging future investigations on the translational potential of ERK5-targeted agents for antineoplastic treatment and chemosensitization.


Authors and Affiliations:

Diane M. Pereira, Sofia. E. Gomes, Pedro M. Borralho, Cecília M. P. Rodrigues

Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal



Colon cancer has been proposed to be sustained by a small subpopulation of stem-like cells with unique properties allowing them to survive conventional therapies and drive tumor recurrence. Identification of targetable signaling pathways contributing to malignant stem-like cell maintenance may therefore translate into new therapeutic strategies to overcome drug resistance. Here, we demonstrated that MEK5/ERK5 signaling activation is associated with stem-like malignant phenotypes. Conversely, using a panel of cell-line derived three-dimensional models, we showed that ERK5 inhibition markedly suppresses the molecular and functional features of colon cancer stem-like cells. Particularly, pharmacological inhibition of ERK5 using XMD8-92 reduced the rate of primary and secondary sphere formation, the expression of pluripotency transcription factors SOX2, NANOG and OCT4, and the proportion of tumor cells with increased ALDH activity. Notably, this was further associated with increased sensitivity to 5-fluorouracil-based chemotherapy. Mechanistically, ERK5 inhibition resulted in decreased IL-8 expression and NF-κB transcriptional activity, suggesting a possible ERK5/NF-κB/IL-8 signaling axis regulating stem-like cell malignancy. Taken together, our results provide proof of principle that ERK5-targeted inhibition may be a promising therapeutic approach to eliminate drug-resistant cancer stem-like cells and improve colon cancer treatment.


Journal: Cell Death Discovery