背景:癌细胞具有极其活跃的代谢,这支持高增殖率。人类结肠癌细胞的代谢谱已被广泛研究,但与非肿瘤同行的比较被忽视。
方法:在这里,我们比较了人结肠腺癌细胞(HT29)和人结肠健康细胞系NCM460中的代谢通量再分布,以确定代谢重编程中涉及的主要途径。此外,我们探索曲古抑菌素A(TSA)对HT29分化的诱导是否使代谢重编程恢复为NCM460。用[1,2-(13)C2]-d-葡萄糖作为示踪剂孵育细胞,和质量异构体分布分析用于表征中心碳代谢的代谢通量分布曲线的变化。
结果:我们证明NCM460中糖酵解速率和磷酸戊糖合成相对于HT29细胞低25%。相比之下,前者的克雷布斯循环活性是后者的两倍。此外,我们显示TSA诱导的HT29细胞分化将代谢表型恢复为健康的NCM460细胞,而TSA不影响NCM460细胞的代谢。
结论:我们得出结论,磷酸戊糖途径,糖酵解,和Krebs周期是结肠腺癌细胞代谢重塑的关键参与者,NCM460是评估旨在选择性靶向代谢重编程的新治疗策略结果的合适模型。
结论:我们的研究结果表明,在癌细胞中抵消强大的代谢适应的策略可能为设计多重命中和靶向治疗开辟新的途径。
BACKGROUND: Cancer cells have extremely active metabolism, which supports high proliferation rates. Metabolic profiles of human colon cancer cells have been extensively studied, but comparison with non-tumour counterparts has been neglected.
METHODS: Here we compared the metabolic flux redistribution in human colon adenocarcinoma cells (HT29) and the human colon healthy cell line NCM460 in order to identify the main pathways involved in metabolic reprogramming. Moreover, we explore if induction of differentiation in HT29 by trichostatin A (TSA) reverts the metabolic reprogramming to that of NCM460. Cells were incubated with [1,2-(13)C2]-d-glucose as a tracer, and Mass Isotopomer Distribution Analysis was applied to characterize the changes in the metabolic flux distribution profile of the central carbon metabolism.
RESULTS: We demonstrate that glycolytic rate and pentose phosphate synthesis are 25% lower in NCM460 with respect to HT29 cells. In contrast, Krebs cycle activity in the former was twice that recorded in the latter. Moreover, we show that TSA-induced HT29 cell differentiation reverts the metabolic phenotype to that of healthy NCM460 cells whereas TSA does not affect the metabolism of NCM460 cells.
CONCLUSIONS: We conclude that pentose phosphate pathway, glycolysis, and Krebs cycle are key players of colon adenocarcinoma cellular metabolic remodeling and that NCM460 is an appropriate model to evaluate the results of new therapeutic strategies aiming to selectively target metabolic reprogramming.
CONCLUSIONS: Our findings suggest that strategies to counteract robust metabolic adaptation in cancer cells might open up new avenues to design multiple hit and targeted therapies.