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1. 5-Fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits

Author

Denise, C, Paoli, P, Calvani, M, Taddei, M, Giannoni, E, Kopetz, S, Kazmi, S, Pia, M, Pettazzoni, P, Sacco, E, Caselli, A, Vanoni, M, Landriscina, M, Cirri, P, Chiarugi, P, Taddei, ML, Kazmi, SMA, Pia, MM, Denise, C, Paoli, P, Calvani, M, Taddei, M, Giannoni, E, Kopetz, S, Kazmi, S, Pia, M, Pettazzoni, P, Sacco, E, Caselli, A, Vanoni, M, Landriscina, M, Cirri, P, Chiarugi, P, Taddei, ML, Kazmi, SMA, and Pia, MM

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.

Published
2015

2. 5-fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits.

Author

Denise C, Paoli P, Calvani M, Taddei ML, Giannoni E, Kopetz S, Kazmi SM, Pia MM, Pettazzoni P, Sacco E, Caselli A, Vanoni M, Landriscina M, Cirri P, and Chiarugi P

Subjects
Animals, Antineoplastic Combined Chemotherapy Protocols pharmacology, Antioxidants metabolism, Biomarkers, Tumor metabolism, Carrier Proteins metabolism, Cell Proliferation drug effects, Colonic Neoplasms metabolism, Colonic Neoplasms pathology, Enzyme Inhibitors pharmacology, Epithelial-Mesenchymal Transition drug effects, Female, HT29 Cells, Humans, Membrane Proteins metabolism, Mice, Nude, Mitochondria drug effects, Mitochondria metabolism, NADP metabolism, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Oxidation-Reduction, Phenotype, Pyruvate Kinase metabolism, Thyroid Hormones metabolism, Time Factors, Tumor Burden drug effects, Xenograft Model Antitumor Assays, Thyroid Hormone-Binding Proteins, Antimetabolites, Antineoplastic pharmacology, Colonic Neoplasms drug therapy, Drug Resistance, Neoplasm, Fluorouracil pharmacology, Neoplastic Stem Cells drug effects, Oxidative Phosphorylation drug effects
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.

Published
2015
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