Abstract
The MEK5/ERK5 signaling pathway is emerging as an important contributor to colon cancer onset, progression and metastasis; however, its relevance to chemotherapy resistance remains unknown. Here, we evaluated the impact of the MEK5/ERK5 cascade in colon cancer cell sensitivity to 5-fluorouracil (5-FU). Increased ERK5 expression was correlated with poor overall survival in colon cancer patients. In colon cancer cells, 5-FU exposure impaired endogenous KRAS/MEK5/ERK5 expression and/or activation. In turn, MEK5 constitutive activation reduced 5-FU-induced cytotoxicity. Using genetic and pharmacological approaches, we showed that ERK5 inhibition increased caspase-3/7 activity and apoptosis following 5-FU exposure. Mechanistically, this was further associated with increased p53 transcriptional activation of p21 and PUMA. In addition, ERK5 inhibition increased the response of HCT116 p53+/+ cells to 5-FU, but failed to sensitize HCT116 p53−/− cells to the cytotoxic effects of this chemotherapeutic agent, suggesting a p53-dependent axis mediating 5-FU sensitization. Finally, ERK5 inhibition using XMD8-92 was shown to increase the antitumor effects of 5-FU in a murine subcutaneous xenograft model, enhancing apoptosis while markedly reducing tumor growth. Collectively, our results suggest that ERK5-targeted in hibition provides a promising therapeutic approach to overcome resistance to 5-FU-based chemotherapy and improve colon cancer treatment.
Highlights
Over the last five decades, the antimetabolite 5-fluorouracil (5-FU) has been the mainstay of colon cancer therapy, both in adjuvant and metastatic settings [1]
We have recently demonstrated that MEK5 and ERK5 expression is increased in human colon adenomas and adenocarcinomas, and that ERK5 overexpression correlates with increased invasion, as well as with presence of lymph node and distant metastasis [11]
There is clinical evidence supporting that MEK5/ERK5 signaling dysregulation plays an important part in tumorigenesis [11, 12]
Summary
Over the last five decades, the antimetabolite 5-fluorouracil (5-FU) has been the mainstay of colon cancer therapy, both in adjuvant and metastatic settings [1]. Progress in the treatment of colon cancer has been achieved after the introduction of new cytotoxic and targeted agents to the existing 5-FU/leucovorin standard [1, 2]. While response rates to current 5-FU combination therapies may be as high as 50%, the median overall survival for patients with metastatic colon cancer is still limited to, at best, 30 months [5,6,7,8]. A deeper understanding of the signaling pathways mediating 5-FU resistance will importantly nourish the identification of new therapeutic targets and combination strategies that could translate into improved outcomes for colon cancer patients
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