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// Corti Denise 1, 2, * , Paolo Paoli 1, * , Maura Calvani 1 , Maria Letizia Taddei 1 , Elisa Giannoni 1 , Scott Kopetz 2 , Syed Mohammad Ali Kazmi 2 , Morelli Maria Pia 2 , Piergiorgio Pettazzoni 2 , Elena Sacco 3 , Anna Caselli 1 , Marco Vanoni 3 , Matteo Landriscina 4 , Paolo Cirri 1 , Paola Chiarugi 1 1 Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy 2 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 3 SYSBIO Centre for Systems Biology, Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy 4 Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy * These authors have contributed equally to this work Correspondence to: Paola Chiarugi, e-mail: paola.chiarugi@unifi.it Keywords: cancer metabolism, OXPHOS, chemoresistance, metformin, cancer stem cells Received: July 15, 2015 Accepted: October 09, 2015 Published: October 21, 2015 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 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.
Corti et al. (Wed,) studied this question.