5-Fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits
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Corti Denise1,2,*, Paolo Paoli1,*, Maura Calvani1, Maria Letizia Taddei1, Elisa Giannoni1, Scott Kopetz2, Syed Mohammad Ali Kazmi2, Morelli Maria Pia2, Piergiorgio Pettazzoni2, Elena Sacco3, Anna Caselli1, Marco Vanoni3, Matteo Landriscina4, Paolo Cirri1, Paola Chiarugi1
1Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
3SYSBIO Centre for Systems Biology, Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy
4Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
*These authors have contributed equally to this work
Paola Chiarugi, e-mail: [email protected]
Keywords: cancer metabolism, OXPHOS, chemoresistance, metformin, cancer stem cells
Received: July 15, 2015 Accepted: October 09, 2015 Published: October 21, 2015
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 stem-like 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.
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