Abstract:
Cancer cells display enhanced glycolytic activity and impaired oxidative phosphorylation even in the presence of adequate oxygen (Warburg effect). Mitochondrial physiology is a promising hit target for anti-cancer therapy because of its key role in Warburg effect and activating apoptosis in mammalian as well as yeast cells. Overexpression of human p53 in S.cerevisiae leads to cell cycle arrest and apotosis. Apoptosis is yet another regulatory phenomenon that has been conserved from yeast to humans. Escape from apoptosis is one of the hallmarks of tumour cells. It has been demonstrated that the expression of p53 and Bax induces apoptosis in yeast. In the present work we show that how S.cerevisiae escapes from p53 induced apoptosis in fermentable carbon source, whereas in case of non-fermentable carbon source this phenomenon is not observed. To shed the light on this aspect we performed a quantitative proteomic analysis of yeast mitochondria isolated from the cells grown on sucrose (fermentation) and glycerol (respiration) with and without p53 over-expression. Through this approach, we identified a total dataset of 1120 proteins with 1% FDR, of which 239(133+106) proteins are differentially experessed in both conditions. Interestingly, we observed that after over-expression of p53 in sucrose grown yeast cells, a complete set of pentose phosphate pathway (PPP) enzymes is up- regulated in the mitochondria that leads to enhanced mitochondrial NADPH production and ROS quenching. Increased association of a hexose transporter (HXT6) and a hexokinase (HXK2) with the mitochondria of fermenting yeast cells upon over-expression of p53 may direct glucose towards PPP inside the mitochondria. This metabolic control is a key element of apoptotic escape and tumour progression. In conclusion, our results provide the evidence that up- regulated PPP inside the mitochondria is a key to evade apoptosis by S.cerevisiae upon p53 overexpression. An impressive approach would be to study this fermenting yeast apoptotic evasion strategy in mamalian cancer cell lines.
