title: 5-fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits.
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.
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.|Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Corti
authors.initials: C
authors.lastname: Denise
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Paoli
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Calvani
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Taddei
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giannoni
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Syed Mohammad Ali
authors.initials: SM
authors.lastname: Kazmi
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Morelli Maria
authors.initials: MM
authors.lastname: Pia
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: Pettazzoni
authors.affiliation: SYSBIO Centre for Systems Biology, Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Sacco
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Caselli
authors.affiliation: SYSBIO Centre for Systems Biology, Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Vanoni
authors.affiliation: Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Landriscina
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Cirri
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Chiarugi
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010641:Phenotype; D011770:Pyruvate Kinase / Q000378:metabolism; D013963:Thyroid Hormones / Q000378:metabolism; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D000964:Antimetabolites, Antineoplastic; D000975:Antioxidants; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D005472:Fluorouracil; D008565:Membrane Proteins; D009249:NADP; D011770:Pyruvate Kinase; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins
keywords: OXPHOS; cancer metabolism; cancer stem cells; chemoresistance; metformin