B1
Onco-gene induced cellular senescence: a 1H NMR based metabolomics study
Basetti Madhu, Masako Narita, Masashi Narita, John Griffiths
Cancer Research UK, Cambridge Research Institute, Cambridge, UK
Senescence, which is a permanent cell cycle arrest, is thought to act as a fail-safe mechanism to prevent the transformation of pre-neoplastic cell populations. Oncogene induced senescence (OIS) is considered as a tumour suppressing mechanism that shares conceptual and therapeutic similarities with the apoptosis machinery. SA-β-gal activity, elevated P53 and P16 protein levels, coupled with morphological changes and gene expression, are used as senescence markers, though reliable metabolic markers for senescence are still missing. Recent studies showed that OIS cells are metabolically active, even though their cell growth is stably suppressed. Hence there is an active research requirement for metabolic markers that will distinguish senescent cells from normally growing cells.
Here we have undertaken a 1H NMR based metabolomic study of oncogenic RAS and MEK induced senescence in Human Diploid Fibroblasts. Metabolomics is the study of the global variation of metabolites in a cell or organism. Principal Component Analysis (PCA) of metabolite profiles of the cell extracts obtained by 1H NMR spectroscopy showed a clear separation of the normal growing cell groups from the OIS cells, indicating that senescence perturbed cellular metabolism. Further, the PCA metabolomics analysis also showed a clear separation of cell groups in which senescence was induced by different oncogenes, which indicates that the metabolism of senescent cells varies, depending on the gene(s) perturbed, even though all these gene aberrations lead to senescence. This study shows that metabolomics is a valuable tool to analyse the phenotypic effects of gene perturbations in cells, such as OIS.
