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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.

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A network of oncogenes and tumor suppressors regulates the mTORC1-signaling pathway. Growth factors bind and stimulate receptor tyrosine kinases (RTKs), which can activate both the PI3K-Akt and Ras-ERK signaling pathways. These upstream signals inhibit the TSC1-TSC2 complex allowing Rheb to activate mTORC1. Activated mTORC1 phosphorylates two direct substrates, the ribosomal S6 kinases (S6K1 and S6K2), and translation repressors 4E-BP1 and 4E-BP2. Cellular energy depletion results in the activation of AMP-activated protein kinase (AMPK) by the tumor suppressor protein LKB1 serine/threonine kinase. AMPK phosphorylates and enhances the GAP function of TSC2 towards Rheb. In addition, AMPK directly phosphorylates the mTORC1 component raptor. Both events result in the inhibition of mTORC1 in response to energy stress. Within this signaling network lie many oncogenes (depicted in red) and tumor suppressors (depicted in blue).
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Figure 1: A network of oncogenes and tumor suppressors regulates the mTORC1-signaling pathway. Growth factors bind and stimulate receptor tyrosine kinases (RTKs), which can activate both the PI3K-Akt and Ras-ERK signaling pathways. These upstream signals inhibit the TSC1-TSC2 complex allowing Rheb to activate mTORC1. Activated mTORC1 phosphorylates two direct substrates, the ribosomal S6 kinases (S6K1 and S6K2), and translation repressors 4E-BP1 and 4E-BP2. Cellular energy depletion results in the activation of AMP-activated protein kinase (AMPK) by the tumor suppressor protein LKB1 serine/threonine kinase. AMPK phosphorylates and enhances the GAP function of TSC2 towards Rheb. In addition, AMPK directly phosphorylates the mTORC1 component raptor. Both events result in the inhibition of mTORC1 in response to energy stress. Within this signaling network lie many oncogenes (depicted in red) and tumor suppressors (depicted in blue).

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)

A network of oncogenes and tumor suppressors regulates the mTORC1-signaling pathway. Growth factors bind and stimulate receptor tyrosine kinases (RTKs), which can activate both the PI3K-Akt and Ras-ERK signaling pathways. These upstream signals inhibit the TSC1-TSC2 complex allowing Rheb to activate mTORC1. Activated mTORC1 phosphorylates two direct substrates, the ribosomal S6 kinases (S6K1 and S6K2), and translation repressors 4E-BP1 and 4E-BP2. Cellular energy depletion results in the activation of AMP-activated protein kinase (AMPK) by the tumor suppressor protein LKB1 serine/threonine kinase. AMPK phosphorylates and enhances the GAP function of TSC2 towards Rheb. In addition, AMPK directly phosphorylates the mTORC1 component raptor. Both events result in the inhibition of mTORC1 in response to energy stress. Within this signaling network lie many oncogenes (depicted in red) and tumor suppressors (depicted in blue).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: A network of oncogenes and tumor suppressors regulates the mTORC1-signaling pathway. Growth factors bind and stimulate receptor tyrosine kinases (RTKs), which can activate both the PI3K-Akt and Ras-ERK signaling pathways. These upstream signals inhibit the TSC1-TSC2 complex allowing Rheb to activate mTORC1. Activated mTORC1 phosphorylates two direct substrates, the ribosomal S6 kinases (S6K1 and S6K2), and translation repressors 4E-BP1 and 4E-BP2. Cellular energy depletion results in the activation of AMP-activated protein kinase (AMPK) by the tumor suppressor protein LKB1 serine/threonine kinase. AMPK phosphorylates and enhances the GAP function of TSC2 towards Rheb. In addition, AMPK directly phosphorylates the mTORC1 component raptor. Both events result in the inhibition of mTORC1 in response to energy stress. Within this signaling network lie many oncogenes (depicted in red) and tumor suppressors (depicted in blue).
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