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.

5-Fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like trait / Denise, Corti; Paolo, Paoli; Maura, Calvani; Maria Letizia, Taddei; Elisa, Giannoni; Scott, Kopetz; Syed Mohammad Ali, Kazmi; Maria Pia, Morelli; Piergiorgio, Pettazzoni; Elena, Sacco; Anna, Caselli; Marco, Vanoni; Matteo, Landriscina; Paolo, Cirri; Paola, Chiarugi.. - In: ONCOTARGET. - ISSN 1949-2553. - ELETTRONICO. - 6:(2015), pp. 41706-41721. [10.18632/oncotarget.5991]

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

PAOLI, PAOLO;CALVANI, MAURA;TADDEI, MARIA LETIZIA;GIANNONI, ELISA;CASELLI, ANNA;CIRRI, PAOLO;CHIARUGI, PAOLA
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.
2015
6
41706
41721
Goal 3: Good health and well-being
Denise, Corti; Paolo, Paoli; Maura, Calvani; Maria Letizia, Taddei; Elisa, Giannoni; Scott, Kopetz; Syed Mohammad Ali, Kazmi; Maria Pia, Morelli; Piergiorgio, Pettazzoni; Elena, Sacco; Anna, Caselli; Marco, Vanoni; Matteo, Landriscina; Paolo, Cirri; Paola, Chiarugi.
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1010836
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