Limits...
Appetite for destruction: the inhibition of glycolysis as a therapy for tuberous sclerosis complex-related tumors.

Csibi A, Blenis J - BMC Biol. (2011)

Bottom Line: The elevated metabolic requirements of cancer cells reflect their rapid growth and proliferation and are met through mutations in oncogenes and tumor suppressor genes that reprogram cellular processes.For example, in tuberous sclerosis complex (TSC)-related tumors, the loss of TSC1/2 function causes constitutive mTORC1 activity, which stimulates glycolysis, resulting in glucose addiction in vitro.In research published in Cell and Bioscience, Jiang and colleagues show that pharmacological restriction of glucose metabolism decreases tumor progression in a TSC xenograft model.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cell Biology, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USA.

ABSTRACT
The elevated metabolic requirements of cancer cells reflect their rapid growth and proliferation and are met through mutations in oncogenes and tumor suppressor genes that reprogram cellular processes. For example, in tuberous sclerosis complex (TSC)-related tumors, the loss of TSC1/2 function causes constitutive mTORC1 activity, which stimulates glycolysis, resulting in glucose addiction in vitro. In research published in Cell and Bioscience, Jiang and colleagues show that pharmacological restriction of glucose metabolism decreases tumor progression in a TSC xenograft model.

Show MeSH

Related in: MedlinePlus

The mTORC1 pathway controls cellular metabolism. The mTORC1 signaling pathway controls metabolic pathways active in proliferating cells. This schematic shows our current understanding of how glycolysis, oxidative phosphorylation, the pentose phosphate pathway (PPP), and glutamine metabolism are interconnected in proliferating cells. The mTORC1 pathway participates in this metabolic rewiring by controlling the expression of genes (depicted in blue) encoding enzymes involved in glycolysis, the PPP, and lipid synthesis. This metabolic control requires the up-regulation of c-Myc and HIF1α (glycolysis), and SREBP1 (lipid biosynthesis and the PPP). mTORC1-dependent metabolic regulation allows for production of both NADPH and intermediates for macromolecular synthesis (depicted in red). c-Myc drives glutamine metabolism, which also supports NADH production.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3198763&req=5

Figure 2: The mTORC1 pathway controls cellular metabolism. The mTORC1 signaling pathway controls metabolic pathways active in proliferating cells. This schematic shows our current understanding of how glycolysis, oxidative phosphorylation, the pentose phosphate pathway (PPP), and glutamine metabolism are interconnected in proliferating cells. The mTORC1 pathway participates in this metabolic rewiring by controlling the expression of genes (depicted in blue) encoding enzymes involved in glycolysis, the PPP, and lipid synthesis. This metabolic control requires the up-regulation of c-Myc and HIF1α (glycolysis), and SREBP1 (lipid biosynthesis and the PPP). mTORC1-dependent metabolic regulation allows for production of both NADPH and intermediates for macromolecular synthesis (depicted in red). c-Myc drives glutamine metabolism, which also supports NADH production.

Mentions: In normal cells the switch from a non-proliferating state, in which oxidative phosphorylation meets the cell's energy needs, to proliferation, in which glycolysis dominates, is triggered by growth factors acting through the mammalian Target of Rapamycin Complex 1 (mTORC1) signaling pathway (Figure 1). This pathway allows cells to integrate information about environmental conditions and to balance catabolic and anabolic processes accordingly. Growth factor-activated kinases phosphorylate and inhibit the tumor sclerosis complex TSC1-TSC2, allowing the small G protein Rheb to activate mTORC1. In addition, mTORC1 is sensitive to intracellular energy levels through the AMP-activated protein kinase (AMPK). In response to energy deprivation, AMPK phosphorylates TSC2, and the mTORC1 component raptor, resulting in mTORC1 inhibition and a reduction of energy consumption [4] (Figure 1). The most recognized function for mTORC1 is the promotion of protein synthesis through the phosphorylation of at least two direct downstream targets, the ribosomal S6 kinases (S6K1 and S6K2), and the translation repressors eIF4E-binding proteins 1 and 2 (4E-BP1 and 4E-BP2) [4] (Figure 1). However, studies using the mTORC1-specific inhibitor rapamycin have revealed a broader role of mTORC1 in regulating the metabolic processes that support cell growth and proliferation (Figure 2).


Appetite for destruction: the inhibition of glycolysis as a therapy for tuberous sclerosis complex-related tumors.

Csibi A, Blenis J - BMC Biol. (2011)

The mTORC1 pathway controls cellular metabolism. The mTORC1 signaling pathway controls metabolic pathways active in proliferating cells. This schematic shows our current understanding of how glycolysis, oxidative phosphorylation, the pentose phosphate pathway (PPP), and glutamine metabolism are interconnected in proliferating cells. The mTORC1 pathway participates in this metabolic rewiring by controlling the expression of genes (depicted in blue) encoding enzymes involved in glycolysis, the PPP, and lipid synthesis. This metabolic control requires the up-regulation of c-Myc and HIF1α (glycolysis), and SREBP1 (lipid biosynthesis and the PPP). mTORC1-dependent metabolic regulation allows for production of both NADPH and intermediates for macromolecular synthesis (depicted in red). c-Myc drives glutamine metabolism, which also supports NADH production.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198763&req=5

Figure 2: The mTORC1 pathway controls cellular metabolism. The mTORC1 signaling pathway controls metabolic pathways active in proliferating cells. This schematic shows our current understanding of how glycolysis, oxidative phosphorylation, the pentose phosphate pathway (PPP), and glutamine metabolism are interconnected in proliferating cells. The mTORC1 pathway participates in this metabolic rewiring by controlling the expression of genes (depicted in blue) encoding enzymes involved in glycolysis, the PPP, and lipid synthesis. This metabolic control requires the up-regulation of c-Myc and HIF1α (glycolysis), and SREBP1 (lipid biosynthesis and the PPP). mTORC1-dependent metabolic regulation allows for production of both NADPH and intermediates for macromolecular synthesis (depicted in red). c-Myc drives glutamine metabolism, which also supports NADH production.
Mentions: In normal cells the switch from a non-proliferating state, in which oxidative phosphorylation meets the cell's energy needs, to proliferation, in which glycolysis dominates, is triggered by growth factors acting through the mammalian Target of Rapamycin Complex 1 (mTORC1) signaling pathway (Figure 1). This pathway allows cells to integrate information about environmental conditions and to balance catabolic and anabolic processes accordingly. Growth factor-activated kinases phosphorylate and inhibit the tumor sclerosis complex TSC1-TSC2, allowing the small G protein Rheb to activate mTORC1. In addition, mTORC1 is sensitive to intracellular energy levels through the AMP-activated protein kinase (AMPK). In response to energy deprivation, AMPK phosphorylates TSC2, and the mTORC1 component raptor, resulting in mTORC1 inhibition and a reduction of energy consumption [4] (Figure 1). The most recognized function for mTORC1 is the promotion of protein synthesis through the phosphorylation of at least two direct downstream targets, the ribosomal S6 kinases (S6K1 and S6K2), and the translation repressors eIF4E-binding proteins 1 and 2 (4E-BP1 and 4E-BP2) [4] (Figure 1). However, studies using the mTORC1-specific inhibitor rapamycin have revealed a broader role of mTORC1 in regulating the metabolic processes that support cell growth and proliferation (Figure 2).

Bottom Line: The elevated metabolic requirements of cancer cells reflect their rapid growth and proliferation and are met through mutations in oncogenes and tumor suppressor genes that reprogram cellular processes.For example, in tuberous sclerosis complex (TSC)-related tumors, the loss of TSC1/2 function causes constitutive mTORC1 activity, which stimulates glycolysis, resulting in glucose addiction in vitro.In research published in Cell and Bioscience, Jiang and colleagues show that pharmacological restriction of glucose metabolism decreases tumor progression in a TSC xenograft model.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cell Biology, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USA.

ABSTRACT
The elevated metabolic requirements of cancer cells reflect their rapid growth and proliferation and are met through mutations in oncogenes and tumor suppressor genes that reprogram cellular processes. For example, in tuberous sclerosis complex (TSC)-related tumors, the loss of TSC1/2 function causes constitutive mTORC1 activity, which stimulates glycolysis, resulting in glucose addiction in vitro. In research published in Cell and Bioscience, Jiang and colleagues show that pharmacological restriction of glucose metabolism decreases tumor progression in a TSC xenograft model.

Show MeSH
Related in: MedlinePlus