5-Fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits

Corti Denise, Paolo Paoli, Maura Calvani, Maria Letizia Taddei, Elisa Giannoni, Scott Kopetz, Syed Mohammad Ali Kazmi, Morelli Maria Pia, Piergiorgio Pettazzoni, Elena Sacco, Anna Caselli, Marco Vanoni, Matteo Landriscina, Paolo Cirri, Paola Chiarugi

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Despite marked tumor shrinkage after 5-FU treatment, the frequency of colon cancer relapse indicates that a fraction of tumor cells survives treatment causing tumor recurrence. The majority of cancer cells divert metabolites into anabolic pathways through Warburg behavior giving an advantage in terms of tumor growth. Here, we report that treatment of colon cancer cell with 5-FU selects for cells with mesenchymal stem-like properties that undergo a metabolic reprogramming resulting in addiction to OXPHOS to meet energy demands. 5-FU treatment-resistant cells show a de novo expression of pyruvate kinase M1 (PKM1) and repression of PKM2, correlating with repression of the pentose phosphate pathway, decrease in NADPH level and in antioxidant defenses, promoting PKM2 oxidation and acquisition of stemlike phenotype. Response to 5-FU in a xenotransplantation model of human colon cancer confirms activation of mitochondrial function. Combined treatment with 5-FU and a pharmacological inhibitor of OXPHOS abolished the spherogenic potential of colon cancer cells and diminished the expression of stem-like markers. These findings suggest that inhibition of OXPHOS in combination with 5-FU is a rational combination strategy to achieve durable treatment response in colon cancer.

Original languageEnglish (US)
Pages (from-to)41706-41721
Number of pages16
JournalOncotarget
Volume6
Issue number39
DOIs
StatePublished - Jan 1 2015

Keywords

  • Cancer metabolism
  • Cancer stem cells
  • Chemoresistance
  • Metformin
  • OXPHOS

ASJC Scopus subject areas

  • Oncology

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    Denise, C., Paoli, P., Calvani, M., Taddei, M. L., Giannoni, E., Kopetz, S., Kazmi, S. M. A., Pia, M. M., Pettazzoni, P., Sacco, E., Caselli, A., Vanoni, M., Landriscina, M., Cirri, P., & Chiarugi, P. (2015). 5-Fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits. Oncotarget, 6(39), 41706-41721. https://doi.org/10.18632/oncotarget.5991