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

Bianchi G, Martella R, Ravera S, Marini C, Capitanio S, Orengo A, Emionite L, Lavarello C, Amaro A, Petretto A, Pfeffer U, Sambuceti G, Pistoia V, Raffaghello L, Longo VD - Oncotarget (2015)

Bottom Line: STS potentiated the effects of OXP on the suppression of colon carcinoma growth and glucose uptake in both in vitro and in vivo models.The STS-dependent increase in both Complex I and Complex II-dependent O(2) consumption was associated with increased oxidative stress and reduced ATP synthesis.Chemotherapy caused additional toxicity, which was associated with increased succinate/Complex II-dependent O(2) consumption, elevated oxidative stress and apoptosis .These findings indicate that the glucose and amino acid deficiency conditions imposed by STS promote an anti-Warburg effect characterized by increased oxygen consumption but failure to generate ATP, resulting in oxidative damage and apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio di Oncologia Istituto G. Gaslini, Genoa, Italy.

ABSTRACT
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. We tested the cytotoxicity of Oxaliplatin (OXP) combined with a 48hour STS on the progression of CT26 colorectal tumors. STS potentiated the effects of OXP on the suppression of colon carcinoma growth and glucose uptake in both in vitro and in vivo models. In CT26 cells, STS down-regulated aerobic glycolysis, and glutaminolysis, while increasing oxidative phosphorylation. The STS-dependent increase in both Complex I and Complex II-dependent O(2) consumption was associated with increased oxidative stress and reduced ATP synthesis. Chemotherapy caused additional toxicity, which was associated with increased succinate/Complex II-dependent O(2) consumption, elevated oxidative stress and apoptosis .These findings indicate that the glucose and amino acid deficiency conditions imposed by STS promote an anti-Warburg effect characterized by increased oxygen consumption but failure to generate ATP, resulting in oxidative damage and apoptosis.

No MeSH data available.


Related in: MedlinePlus

Effect of STS in combination with chemotherapy on oxidative phosphorylation activity of CT26 colon carcinoma cellsPanels A, B and C report the activity of the redox Complexes I, II and IV in CT26 cell lines treated with STS +/− OXP. Data are expressed as mean values ± SD. P value was calculated using unpaired t-test with Welch's correction. *: P<0.05. Panels D-E show the oxygen consumption rate (OCR) of CT26 in the presence of pyruvate (10mM)/malate (5mM) and succinate (20mM), respectively. OCR was measured by an oxygen micro-respiration electrode and expressed as μM O2/min/106 cells. Each is representative of at least three experiments. Panels F-G describe the activity of F0-F1 ATP synthase of CT26 cell lines, measured by luminometric analysis, after the addition of 10 mM pyruvate + 5 mM malate or 20 mM succinate. Panels H-I show the OCR and ATP synthesis in CT26 cells in the presence of pyruvate (10mM)/malate (5mM) and pre-incubated with Rotenone. Each is representative of at least six experiments. P value was calculated using unpaired t-test with Welch's correction. *: P<0.05.
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Figure 4: Effect of STS in combination with chemotherapy on oxidative phosphorylation activity of CT26 colon carcinoma cellsPanels A, B and C report the activity of the redox Complexes I, II and IV in CT26 cell lines treated with STS +/− OXP. Data are expressed as mean values ± SD. P value was calculated using unpaired t-test with Welch's correction. *: P<0.05. Panels D-E show the oxygen consumption rate (OCR) of CT26 in the presence of pyruvate (10mM)/malate (5mM) and succinate (20mM), respectively. OCR was measured by an oxygen micro-respiration electrode and expressed as μM O2/min/106 cells. Each is representative of at least three experiments. Panels F-G describe the activity of F0-F1 ATP synthase of CT26 cell lines, measured by luminometric analysis, after the addition of 10 mM pyruvate + 5 mM malate or 20 mM succinate. Panels H-I show the OCR and ATP synthesis in CT26 cells in the presence of pyruvate (10mM)/malate (5mM) and pre-incubated with Rotenone. Each is representative of at least six experiments. P value was calculated using unpaired t-test with Welch's correction. *: P<0.05.

Mentions: Proteomic and genomic analyses did not show a clear effect of STS in up- regulating OXPHOS although different sets of respiratory enzymes were elevated after STS or OXP or STS+OXP (Supplementary Figure 2A-B). Clear changes were instead observed when measuring enzymatic activities of respiratory complexes, oxygen consumption and ATP: STS up-regulated Complex I and IV (Figure 4A and C) without affecting Complex II activity (Figure 4B). Consistent with this effect, a significant increase in O2consumption rate (OCR), indicative of an increased oxidative metabolism, was observed (Figure 4D and E). This corresponded to a significant reduction of ATP synthesis (Figure 4F and G). Accordingly, the ATP/AMP ratio, a good indicator of cellular energy charge, was dramatically reduced by the two STS settings (Supplementary Figure 2C).


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

Bianchi G, Martella R, Ravera S, Marini C, Capitanio S, Orengo A, Emionite L, Lavarello C, Amaro A, Petretto A, Pfeffer U, Sambuceti G, Pistoia V, Raffaghello L, Longo VD - Oncotarget (2015)

Effect of STS in combination with chemotherapy on oxidative phosphorylation activity of CT26 colon carcinoma cellsPanels A, B and C report the activity of the redox Complexes I, II and IV in CT26 cell lines treated with STS +/− OXP. Data are expressed as mean values ± SD. P value was calculated using unpaired t-test with Welch's correction. *: P<0.05. Panels D-E show the oxygen consumption rate (OCR) of CT26 in the presence of pyruvate (10mM)/malate (5mM) and succinate (20mM), respectively. OCR was measured by an oxygen micro-respiration electrode and expressed as μM O2/min/106 cells. Each is representative of at least three experiments. Panels F-G describe the activity of F0-F1 ATP synthase of CT26 cell lines, measured by luminometric analysis, after the addition of 10 mM pyruvate + 5 mM malate or 20 mM succinate. Panels H-I show the OCR and ATP synthesis in CT26 cells in the presence of pyruvate (10mM)/malate (5mM) and pre-incubated with Rotenone. Each is representative of at least six experiments. P value was calculated using unpaired t-test with Welch's correction. *: P<0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494906&req=5

Figure 4: Effect of STS in combination with chemotherapy on oxidative phosphorylation activity of CT26 colon carcinoma cellsPanels A, B and C report the activity of the redox Complexes I, II and IV in CT26 cell lines treated with STS +/− OXP. Data are expressed as mean values ± SD. P value was calculated using unpaired t-test with Welch's correction. *: P<0.05. Panels D-E show the oxygen consumption rate (OCR) of CT26 in the presence of pyruvate (10mM)/malate (5mM) and succinate (20mM), respectively. OCR was measured by an oxygen micro-respiration electrode and expressed as μM O2/min/106 cells. Each is representative of at least three experiments. Panels F-G describe the activity of F0-F1 ATP synthase of CT26 cell lines, measured by luminometric analysis, after the addition of 10 mM pyruvate + 5 mM malate or 20 mM succinate. Panels H-I show the OCR and ATP synthesis in CT26 cells in the presence of pyruvate (10mM)/malate (5mM) and pre-incubated with Rotenone. Each is representative of at least six experiments. P value was calculated using unpaired t-test with Welch's correction. *: P<0.05.
Mentions: Proteomic and genomic analyses did not show a clear effect of STS in up- regulating OXPHOS although different sets of respiratory enzymes were elevated after STS or OXP or STS+OXP (Supplementary Figure 2A-B). Clear changes were instead observed when measuring enzymatic activities of respiratory complexes, oxygen consumption and ATP: STS up-regulated Complex I and IV (Figure 4A and C) without affecting Complex II activity (Figure 4B). Consistent with this effect, a significant increase in O2consumption rate (OCR), indicative of an increased oxidative metabolism, was observed (Figure 4D and E). This corresponded to a significant reduction of ATP synthesis (Figure 4F and G). Accordingly, the ATP/AMP ratio, a good indicator of cellular energy charge, was dramatically reduced by the two STS settings (Supplementary Figure 2C).

Bottom Line: STS potentiated the effects of OXP on the suppression of colon carcinoma growth and glucose uptake in both in vitro and in vivo models.The STS-dependent increase in both Complex I and Complex II-dependent O(2) consumption was associated with increased oxidative stress and reduced ATP synthesis.Chemotherapy caused additional toxicity, which was associated with increased succinate/Complex II-dependent O(2) consumption, elevated oxidative stress and apoptosis .These findings indicate that the glucose and amino acid deficiency conditions imposed by STS promote an anti-Warburg effect characterized by increased oxygen consumption but failure to generate ATP, resulting in oxidative damage and apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio di Oncologia Istituto G. Gaslini, Genoa, Italy.

ABSTRACT
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. We tested the cytotoxicity of Oxaliplatin (OXP) combined with a 48hour STS on the progression of CT26 colorectal tumors. STS potentiated the effects of OXP on the suppression of colon carcinoma growth and glucose uptake in both in vitro and in vivo models. In CT26 cells, STS down-regulated aerobic glycolysis, and glutaminolysis, while increasing oxidative phosphorylation. The STS-dependent increase in both Complex I and Complex II-dependent O(2) consumption was associated with increased oxidative stress and reduced ATP synthesis. Chemotherapy caused additional toxicity, which was associated with increased succinate/Complex II-dependent O(2) consumption, elevated oxidative stress and apoptosis .These findings indicate that the glucose and amino acid deficiency conditions imposed by STS promote an anti-Warburg effect characterized by increased oxygen consumption but failure to generate ATP, resulting in oxidative damage and apoptosis.

No MeSH data available.


Related in: MedlinePlus