title: Protection against cisplatin in calorie-restricted Saccharomyces cerevisiae is mediated by the nutrient-sensor proteins Ras2, Tor1, or Sch9 through its target glutathione.
abstract: There is substantial interest in developing alternative strategies for cancer chemotherapy aiming to increase drug specificity and prevent tumor resistance. Calorie restriction (CR) has been shown to render human cancer cells more susceptible to drugs than normal cells. Indeed, deficiency of nutrient signaling proteins mimics CR, which is sufficient to improve oxidative stress response and life expectancy only in healthy cells. Thus, although CR and reduction of nutrient signaling may play an important role in cellular response to chemotherapy, the full underlying mechanisms are still not completely understood. Here, we investigate the relationship between the nutrient sensor proteins Ras2, Sch9, or Tor1 and the response of calorie-restricted Saccharomyces cerevisiae cells to cisplatin. Using wild-type and nutrient-sensing mutant strains, we show that deletion of any of these proteins mimics CR and is sufficient to increase cell protection. Moreover, we show that glutathione (GSH) is essential for proper CR protection of yeast cells under cisplatin chemotherapy. By measuring the survival rates and GSH levels, we found that cisplatin cytotoxicity leads to a decrease in GSH content reflecting in an increase of oxidative damage. Finally, investigating DNA fragmentation and apoptosis, we conclude that GSH contributes to CR-mediated cell survival.
authors.affiliation: Departamento de Bioquímica, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
authors.forename: Diana
authors.initials: D
authors.lastname: Mariani
authors.forename: Frederico A V
authors.initials: FA
authors.lastname: Castro
authors.forename: Luciana G
authors.initials: LG
authors.lastname: Almeida
authors.forename: Fernanda L
authors.initials: FL
authors.lastname: Fonseca
authors.forename: Marcos D
authors.initials: MD
authors.lastname: Pereira
mesh_terms: D017209:Apoptosis; D002945:Cisplatin / Q000633:toxicity*; D053938:DNA Fragmentation; D017353:Gene Deletion; D005978:Glutathione / Q000378:metabolism*; D050296:Microbial Viability / Q000187:drug effects; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D002945:Cisplatin; D005978:Glutathione; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D029701:Saccharomyces cerevisiae Proteins; D018631:ras Proteins; C083324:TOR1 protein, S cerevisiae; C530964:SCH9 protein, S cerevisiae; C489015:RAS2 protein, S cerevisiae
keywords: Ras2, Sch9, or Tor1; Saccharomyces cerevisiae; calorie restriction; cisplatin; glutathione