Caloric Restriction Mimetics: Metabolic Interventions

Weindruch, Richard; Keenan, Kevin P.; Carney, John M.; Fernandes, Gabriel; Feuers, Ritchie J.; Floyd, Robert A.; Halter, Jeffrey B.; Ramsey, Jon J.; Richardson, Arlan; Roth, George S.; Spindler, Stephen R.

doi:10.1093/gerona/56.suppl_1.20

Cited by 127 publications

(80 citation statements)

References 123 publications

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“…50 In contrast to 0.2% glucose, which induced the Gad8-S546 phosphorylation in glucosestarved cells, the same concentration of 2-DG failed to recover the Gad8 phosphorylation at all (Fig. 2D).…”

Section: Torc2 Remains Active During Nitrogen Starvationmentioning

confidence: 85%

Fission yeast Ryh1 GTPase activates TOR Complex 2 in response to glucose

et al. 2015

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The Target Of Rapamycin (TOR) is an evolutionarily conserved protein kinase that forms 2 distinct protein complexes referred to as TOR complex 1 (TORC1) and 2 (TORC2). Recent extensive studies have demonstrated that TORC1 is under the control of the small GTPases Rheb and Rag that funnel multiple input signals including those derived from nutritional sources; however, information is scarce as to the regulation of TORC2. A previous study using the model system provided by the fission yeast Schizosaccharomyces pombe identified Ryh1, a Rab-family GTPase, as an activator of TORC2. Here, we show that the nucleotide-binding state of Ryh1 is regulated in response to glucose, mediating this major nutrient signal to TORC2. In glucose-rich growth media, the GTP-bound form of Ryh1 induces TORC2-dependent phosphorylation of Gad8, a downstream target of TORC2 in fission yeast. Upon glucose deprivation, Ryh1 becomes inactive, which turns off the TORC2-Gad8 pathway. During glucose starvation, however, Gad8 phosphorylation by TORC2 gradually recovers independently of Ryh1, implying an additional TORC2 activator that is regulated negatively by glucose. The paired positive and negative regulatory mechanisms may allow fine-tuning of the TORC2-Gad8 pathway, which is essential for growth under glucose-limited environment.

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Section: Torc2 Remains Active During Nitrogen Starvationmentioning

confidence: 85%

Fission yeast Ryh1 GTPase activates TOR Complex 2 in response to glucose

et al. 2015

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“…Upon transport into the cells, 2-DG is phosphorylated by hexokinase to 2-DG-P. However, unlike G-6-P, 2-DG-P cannot be further metabolized by phosphohexose isomerase, which converts G-6-P to fructose-6-phosphate (Weindruch et al, 2001). 2-Deoxyglucose-P is trapped and accumulated in the cells, leading to inhibition of glycolysis mainly at the step of phosphorylation of glucose by hexokinase.…”

Section: -Deoxyglucosementioning

confidence: 99%

Glycolysis inhibition for anticancer treatment

et al. 2006

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Most cancer cells exhibit increased glycolysis and use this metabolic pathway for generation of ATP as a main source of their energy supply. This phenomenon is known as the Warburg effect and is considered as one of the most fundamental metabolic alterations during malignant transformation. In recent years, there are significant progresses in our understanding of the underlying mechanisms and the potential therapeutic implications. Biochemical and molecular studies suggest several possible mechanisms by which this metabolic alteration may evolve during cancer development. These mechanisms include mitochondrial defects and malfunction, adaptation to hypoxic tumor microenvironment, oncogenic signaling, and abnormal expression of metabolic enzymes. Importantly, the increased dependence of cancer cells on glycolytic pathway for ATP generation provides a biochemical basis for the design of therapeutic strategies to preferentially kill cancer cells by pharmacological inhibition of glycolysis. Several small molecules have emerged that exhibit promising anticancer activity in vitro and in vivo, as single agent or in combination with other therapeutic modalities. The glycolytic inhibitors are particularly effective against cancer cells with mitochondrial defects or under hypoxic conditions, which are frequently associated with cellular resistance to conventional anticancer drugs and radiation therapy. Because increased aerobic glycolysis is commonly seen in a wide spectrum of human cancers and hypoxia is present in most tumor microenvironment, development of novel glycolytic inhibitors as a new class of anticancer agents is likely to have broad therapeutic applications.

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“…However, unlike glucose-PO4, the 2-DG-PO4 cannot further be metabolized by the GPI. In addition, 2-DG could inhibit GPI (47), and then down-regulate its downstream glycolysis-related genes. Consistent with results from the glycolytic pathway regulated by 2-DG, our data revealed that the upstream genes of GLUT1 and HK1 are overexpressed subsequent to 2-DG administration, and the downstream genes of GPI, GAPD, PGK1, PGK2, ENO2 and PKM2 are underexpressed in CRC cell lines.…”

Section: -------------------------------------------------mentioning

confidence: 99%

Significance of the glycolytic pathway and glycolysis related-genes in tumorigenesis of human colorectal cancers

Yeh

Wang²,

Chung³

et al. 2008

Oncol Rep

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Abstract. We investigated gene expressions involved in the glycolytic pathways in colorectal cancer. The study was designed to use gene ontology and its relevant bioinformatics tools to analyze the microarray data obtained from CRC tissues and their corresponding normal tissues, in order to explore the correlation between the glycolytic metabolic pathway and possible pathogenesis of this disease. The overexpression of glycolysis-related genes was observed in over 76% of CRC tissues. In addition, we stimulated the SW480 and SW620 CRC cell lines with 15 mM D-(+)-glucose and 10 mM 2-deoxy-D-glucose respectively. The results indicate that the proliferation response of both the SW480 and SW620 cell lines increased remarkably with a time-dependent effect by D-(+)-glucose administration. In contrast, the proliferation response of both the SW480 and SW620 cell lines was significantly inhibited by 2-DG administration. Likewise, further analyses of the expression of related genes triggered by the D-(+)-glucose in vivo show that the activation process of these eight genes -GLUT1, HK1, GPI, GAPD, PGK1, PGK2, ENO2, PKM2 -prominently increased with a timedependent effect. In conclusion, this study demonstrates that the glycolytic pathway and glycolysis-related genes may play an important role in the tumorigenesis of CRC, but their molecular mechanisms need further investigation to verify this.

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Caloric Restriction Mimetics: Metabolic Interventions

Cited by 127 publications

References 123 publications

Fission yeast Ryh1 GTPase activates TOR Complex 2 in response to glucose

Fission yeast Ryh1 GTPase activates TOR Complex 2 in response to glucose

Glycolysis inhibition for anticancer treatment

Significance of the glycolytic pathway and glycolysis related-genes in tumorigenesis of human colorectal cancers

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