Search

Abstract: Many cancer cells are characterized by high rate of glycolysis and reduced rate of aerobic respiration, whose mechanism is still elusive. Here we investigate the down-regulation of oxidative phosphorylation (OXPHOS) in K-ras transformed mouse fibroblasts as compared to a control counterpart. Transcriptional analysis showed different expression levels of several OXPHOS nuclear genes in the two cell lines. In particular, during the exponential growth phase most genes encoding proteins of Complex I were expressed at lower levels in transformed cells. Consistently, a significant decrease of Complex I content was found in transformed cells. Moreover, analysis of NAD-dependent respiration and ATP synthesis indicated a strong decrease of Complex I activity in the mitochondria from neoplastic cells, that was confirmed by direct assay of the enzyme redox activity. At variance, succinate-dependent respiration and ATP synthesis were not significantly affected. Taken together, our results provide the new insight that the reduction of respiration observed in K-ras transformed cells is specifically due to a Complex I activity decrease. [Copyright &y& Elsevier]

Abstract: K-ras transformed fibroblasts have been shown to have a stronger dependence from glycolysis, reduced oxidative phosphorylation ability and a fragility towards glucose depletion compared to their immortalized, normal counterparts. In this paper, using RNA profiling assays and metabolic perturbations, we report changes in expression of genes encoding mitochondrial proteins and alterations in mitochondrial morphology that correlate with mitochondrial functionality. In fact, unlike normal cells, transformed cells show reduced ATP content and inability to modify mitochondria morphology upon glucose depletion. Being reverted by GEF-DN expression, such morphological and functional changes are directly connected to Ras activation. Taken together with reported partial mitochondrial uncoupling and more sustained apoptosis of transformed cells, our results indicate that activation of the Ras pathway strikingly impacts on energy and signaling-related aspects of mitochondria functionality, that in turn may affect the terminal phenotype of transformed cells. [Copyright &y& Elsevier]