5-fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits.
5-fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits.
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DOI：
10.18632/oncotarget.5991
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发表时间：
2015-12-08
期刊：
影响因子：
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通讯作者：
Chiarugi P
中科院分区：
文献类型：
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作者：
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;Chiarugi P
尽管5-FU治疗后肿瘤明显缩小，但结肠癌复发的频率表明，一小部分肿瘤细胞在治疗后存活，导致肿瘤复发。大多数癌细胞通过Warburg行为将代谢物转移到合成代谢途径，这在肿瘤生长方面具有优势。在这里，我们报道用5-FU治疗结肠癌细胞选择具有间充质干细胞样特性的细胞，这些细胞经历代谢重编程，导致对OXPHOS成瘾以满足能量需求。5-FU处理抗性细胞显示丙酮酸激酶M1 （PKM1）的重新表达和PKM2的抑制，与戊糖磷酸途径的抑制、NADPH水平的降低和抗氧化防御相关，促进PKM2氧化和获得茎样表型。在人类结肠癌异种移植模型中对5-FU的反应证实了线粒体功能的激活。5-FU和OXPHOS药物抑制剂联合治疗可消除结肠癌细胞的成球潜能，并降低干细胞样标志物的表达。这些发现表明，抑制OXPHOS联合5-FU是一种合理的联合策略，可以在结肠癌中实现持久的治疗反应。
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.