Abstract
Cellular senescence displays a heterogeneous set of phenotypes linked to tumor suppression; however, after drug treatment, senescence may also be involved in stable or recurrent cancer. Metabolic changes during senescence can provide detailed information on cellular status and may also have implications for the development of effective treatment strategies. The metabolic response to Adriamycin (ADR) treatment, which causes senescence as well as cell death, was obtained with the aid of metabolic profiling and isotope tracing in two human breast cancer cell lines, MCF7 and MDA-MB-231. After 5 days of ADR treatment, more than 60% of remaining, intact cells entered into a senescent state, characterized by enlarged and flattened morphology and positive blue staining using SA-β-gal. Metabolic trajectory analysis showed that the two cell lines' responses were significantly different and were divided into two distinct stages. The metabolic shift from the first stage to the second was reflected by a partial recovery of the TCA cycle, as well as amino acid and lipid metabolisms. Isotope tracing analysis indicated that the higher level of glutamine metabolism helped maintain senescence. The results suggest that the dynamic changes during senescence indicate a multi-step process involving important metabolic pathways which might allow breast cancer cells to adapt to persistent ADR treatment, while the higher level of anapleurosis may be important for maintaining the senescent state. Ultimately, a better understanding of metabolic changes during senescence might provide targets for cancer therapy and tumor eradication.
Keywords:
MDA-MB-231; gas chromatography–mass spectrometry (GC–MS); isotope tracing analysis; metabolomics; senescence MCF7.