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.

miR‐210‐3p mediates metabolic adaptation and sustains DNA damage repair of resistant colon cancer cells to treatment with 5‐fluorouracil

“…We have previously demonstrated that colon cancer‐resistant cells acutely treated with 5‐FU modulate their metabolism and undergo epithelial‐mesenchymal transition, increasing stemness and aggressiveness. Nevertheless, we demonstrated that it is possible to revert resistance of cancer cells by interfering with molecular mechanisms that mediate the adaptive response . Based on this evidence, we speculate that the adaptive response of resistant cells could be modulated by altered miRNA expression.…”

“…To investigate the contribution of miRNAs expression in the acquisition of chemoresistance, we used as a model a HT29 human colon cancer cell line resistant to 5‐FU (HT29R). HT29R cells were obtained exposing HT29 cells to increasing doses of 5‐FU, as previously described . A profiled miRNA expression analysis on microarray platform pointed out 98 of the 382 considered miRNAs differently expressed between HT29 and HT29R cells (Table S1), thereby confirming that resistant cells undergo strong genetic reprogramming.…”

“…Cells were routinely grown in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% fetal bovine serum, glutamine, and penicillin‐streptomycin (Sigma‐Aldrich, St. Louis, MO), in a humidified atmosphere with 5% CO 2 at 37°C. HT29 cells resistant to 5‐FU (HT29R) were selected by exposing HT29 parental cells to increasing doses of 5‐FU during 6 months until the final concentration of 20 µM, as previous described . To ensure the maintenance of resistance to 5‐FU, HT29R cells were treated every 15 days with a single dose of the drug (20 µM 5‐FU) and let them recover for 1 week before performing experiments.…”

Morin‐dependent inhibition of low molecular weight protein tyrosine phosphatase (LMW‐PTP) restores sensitivity to apoptosis during colon carcinogenesis: Studies in vitro and in vivo, in an Apc‐driven model of colon cancer

“…HT29 and HCT‐116 resistant to 5‐FU (HT29R and HCT‐116R, respectively) were selected by exposing HT29 or HCT‐116 sensitive cells to increasing doses of 5‐FU during 6 months until the final concentration of 20 μM, as previously described …”

Ethanolic Extract of Hedyotis corymbosa and Its Combination with 5-FU Inhibit Cyclin D Expression on WiDr Colorectal Cancer Cell

“…The prevalence of colorectal cancer has been incresed along the increasing human population (ACS, 2014). First line therapy for CRC, 5-fluorouracil (5FU) has been become resistence despite its side effect like neutropenia, immunosuppression, cardiotoxicity and diarrhea (Denise, et al, 2015;Gressett, et al, 2006;Sorrentino, et al, 2012). *Corresponding author e-mail : ririsjenie@gmail.com Recently, natural products have received great interest since they have relatively few side effects compared with modern chemotherapeutics and have been used clinically for thousands of years as significant alternative remedies for a variety of diseases including cancer (Kellof, 2000;Jeune, et al, 2005;Won, et al, 2006).…”