基于代谢组学的多西他赛调控肺癌细胞代谢重编程研究

BACKGROUND AND OBJECTIVE: Docetaxel is a commonly used anti-tumor drug in clinic, especially as the first-line drug for advanced non-small cell lung cancer (NSCLC). However, the molecular mechanism of docetaxel against NSCLC is still unclear. Increasing studies have shown that metabolic reprogramming of tumor cells plays an important role in tumorigenesis. The aim of this study was to investigate the effects of docetaxel on the metabolic pathway of NSCLC cells based on metabolomics analysis and biological means. METHODS: First, we performed CCK8 assay to analyze the effects of docetaxel on cell viability of NSCLC cells and also to screen the appropriate drug concentration. Then, the differential metabolites of docetaxel-treated and untreated NSCLC cells were analyzed by gas chromatography-mass spectrometry based metabolomics. Finally, the effects of docetaxel on the expression levels of key enzymes that regulate the relevant metabolic pathways were determined by Western blot. RESULTS: Docetaxel inhibited cell viability of A549 and H1299 cells in a concentration- and time-dependent manner. With the prolonged treatment time of docetaxel, the apoptotic sensitive protein poly (ADP-ribose) polymerase (PARP) was gradually activated to form a P89 fragment. Metabolomics analysis showed that eight metabolites were significantly changed in both A549 and H1299 cells following docetaxel treatment, which were mainly in the tricarboxylic acid (TCA) cycle pathway. Moreover, after docetaxel treatment, the protein expression levels of isocitrate dehydrogenases, the key regulators of the TCA cycle, were obviously decreased in both A549 and H1299 cells. CONCLUSION: Our findings suggest that the effect of docetaxel-induced proliferation inhibition and apoptosis in NSCLC might be associated with down-regulation of isocitrate dehydrogenases and suppression of the TCA cycle pathway.