Unknown,Transcriptomics,Genomics,Proteomics

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Starvation and chemotherapy

ABSTRACT: Tumor chemoresistance is often associated to high aerobic glycolysis rates and reduced oxidative phosphorylation by cancer cells, a phenomenon called the “Warburg effect”. Thus, a treatment reversing the Warburg effect could decrease tumor cell survival both in the presence or absence of chemotherapy. Short-term starvation (STS) could accomplish this task since it is accompanied by a glucose and amino acid decrease and fatty acid increase, which require respiration for energy production. We tested the cytotoxicity of STS+Oxaliplatin on colon cancer cells by Trypan Blue, Carboxyfluorescein Succinimidyl ester and Annexin V staining. Reactive oxygen species production was measured by 2',7'-dichlorodihydrofluorescein diacetate staining. In vitro glucose consumption was evaluated by 18F-Fluoro-deoxyglucose uptake. Gene expression was tested by microarray analysis. Protein expression and activity were studied by western blot, proteomic analyses and spectrophotometric assays. CT26 bearing mice consumed only water for 48 hours (STS) before oxaliplatin treatment. Dynamic micro-Positron Emission Tomography and tumor growth measurements were performed. STS+Oxaliplatin cause a potent suppression of colon carcinoma growth and glucose consumption in in vitro and in vivo models. In CT26 cells, STS down-regulates aerobic glycolysis, and glutaminolysis, while increasing oxidative phosphorylation. STS-dependent increase in O2 consumption is associated with reduced ATP synthesis and increased oxidation. In combination with chemotherapy, these effects of STS cause additive toxicity to cancer cells. Our findings indicate that during and following STS the decreased glucose levels promote an anti-Warburg effect characterized by increased oxygen consumption but failure to generate ATP, resulting in oxidative damage and apoptosis. The experiment comprised for conditions: Control, Starvation, Oxaliplatin, and Starvation plus Oxaliplatin

ORGANISM(S): Mus musculus

SUBMITTER: Ulrich Pfeffer

PROVIDER: E-GEOD-60653 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Fasting induces anti-Warburg effect that increases respiration but reduces ATP-synthesis to promote apoptosis in colon cancer models.

Bianchi Giovanna G Martella Roberto R Ravera Silvia S Marini Cecilia C Capitanio Selene S Orengo Annamaria A Emionite Laura L Lavarello Chiara C Amaro Adriana A Petretto Andrea A Pfeffer Ulrich U Sambuceti Gianmario G Pistoia Vito V Raffaghello Lizzia L Longo Valter D VD

Oncotarget 20150501 14

Tumor chemoresistance is associated with high aerobic glycolysis rates and reduced oxidative phosphorylation, a phenomenon called "Warburg effect" whose reversal could impair the ability of a wide range of cancer cells to survive in the presence or absence of chemotherapy. In previous studies, Short-term-starvation (STS) was shown to protect normal cells and organs but to sensitize different cancer cell types to chemotherapy but the mechanisms responsible for these effects are poorly understood. ...[more]

PMID: 25909219

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Project description:Cultivation methods used to investigate microbial calorie restriction often result in carbon and energy starvation. This study aims to dissect cellular responses to calorie restriction and starvation in Saccharomyces cerevisiae by using retentostat cultivation. In retentostats, cells are continuously supplied with a small, constant carbon and energy supply, sufficient for maintenance of cellular viability and integrity but insufficient for growth. When glucose-limited retentostats cultivated under extreme calorie restriction were subjected to glucose starvation, calorie-restricted and glucose-starved cells were found to share characteristics such as increased heat-shock tolerance and expression of quiescence-related genes. However, they also displayed strikingly different features. While calorie-restricted yeast cultures remained metabolically active and viable for prolonged periods of time, glucose starvation resulted in rapid consumption of reserve carbohydrates, population heterogeneity due to appearance of senescent cells and, ultimately, loss of viability. Moreover, during starvation, calculated rates of ATP synthesis from storage carbohydrates were 2-3 orders of magnitude lower than steady-state ATP-turnover rates calculated under extreme calorie restriction in retentostats. Stringent reduction of ATP turnover during glucose starvation was accompanied by a strong down-regulation of genes involved in protein synthesis. These results demonstrate that extreme calorie restriction and carbon starvation represent different physiological states in S. cerevisiae. The yeast was first grown for 14 days under extreme calorie restriction in anaerobic, glucose-limited retentostats (Boender et al., 2009, Appl.Environ.Microbiol., 75: 5607-5614.). Subsequently, starvation was started by terminating the glucose feed. Yeast transcriptional reprogramming in response to calorie restriction and starvation was monitored by microarray analysis. Independent duplicate retentostat cultures, and subsequently starvation, were sampled for transcriptome analysis using Affymetrix microarrays. One time-point was sampled during calorie restriction (T0) and four time points were sampled during the starvation phase 10, 30, 60 and 120 minutes after switching of the feed, resulting in a dataset of 10 arrays.

Dataset Information

Starvation and chemotherapy

Publications

Fasting induces anti-Warburg effect that increases respiration but reduces ATP-synthesis to promote apoptosis in colon cancer models.

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