Abstract

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.

Highlights

  • The identification of stem-like cells within tumors has reshaped our understanding of cancer development, introducing an additional layer of complexity to the concept of intratumoral heterogeneity[1]

  • Changes in NANOG, OCT4, and SOX2 were confirmed at the protein level (Fig. 1d). These findings demonstrate that MEK5/ERK5 activation correlates with a shift toward an undifferentiated state in colon cancer cells, suggesting that colon cancer stem-like populations may be dependent on ERK5-mediated signaling

  • We demonstrate that MEK5/ERK5 activation is increased in several cell line-derived models enriched for malignant stem cells (Fig. 1); and that ERK5 inhibition using XMD8-92 suppresses both self-renewal and the expression of colon cancer stem cells (CSCs)-associated markers (Figs. 2 and 3)

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Summary

Introduction

The identification of stem-like cells within tumors has reshaped our understanding of cancer development, introducing an additional layer of complexity to the concept of intratumoral heterogeneity[1]. CSC populations are characterized by their remarkable potential to perpetuate themselves through self-renewal, while retaining the ability to differentiate into the full repertoire of neoplastic cells forming the heterogeneous tumor mass[5]. Owing to their highly tumorigenic and adaptable phenotype, colon CSCs are currently recognized as the only subset of neoplastic cells holding attributes for tumor initiation, sustained growth, and metastasis formation[6]. Elucidation of the molecular players regulating stem-like cell maintenance in colon cancer may translate into new therapeutic strategies to overcome drug resistance and avoid tumor recurrence

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