Metformin, Independent of AMPK, Inhibits mTORC1 In a Rag GTPase-Dependent Manner
Identifieur interne : 006F23 ( Main/Exploration ); précédent : 006F22; suivant : 006F24Metformin, Independent of AMPK, Inhibits mTORC1 In a Rag GTPase-Dependent Manner
Auteurs : Adem Kalender [États-Unis, Suisse] ; Anand Selvaraj [États-Unis, Suisse] ; So Young Kim [Suisse, États-Unis] ; Pawan Gulati [États-Unis] ; Sophie Br Lé [Canada] ; Benoit Viollet [France] ; Bruce Kemp [Australie] ; Nabeel Bardeesy [États-Unis] ; Patrick Dennis [États-Unis] ; John J. Schlager [États-Unis] ; André Marette [Canada] ; Sara C. Kozma [États-Unis, Suisse] ; George Thomas [États-Unis, Suisse]Source :
- Cell metabolism [ 1550-4131 ] ; 2010.
Abstract
Dysfunctional mTORC1 signaling is associated with a number of human pathologies owing to its central role in controlling cell growth, proliferation, and metabolism. Regulation of mTORC1 is achieved by the integration of multiple inputs, including those of mitogens, nutrients, and energy. It is thought that agents that increase the cellular AMP/ATP ratio, such as the anti-diabetic biguanides metformin and phenformin, inhibit mTORC1 through AMPK activation of TSC1/2-dependent or -independent mechanisms. Unexpectedly, we found that biguanides inhibit mTORC1 signaling, not only in the absence of TSC1/2, but also in the absence of AMPK. Consistent with these observations, in two distinct pre-clinical models of cancer and diabetes, metformin acts to suppress mTORC1 signaling in an AMPK-independent manner. We found that the ability of biguanides to inhibit mTORC1 activation and signaling is, instead, dependent on the Rag GTPases.
Url:
DOI: 10.1016/j.cmet.2010.03.014
PubMed: 20444419
PubMed Central: 3081779
Affiliations:
- Australie, Canada, France, Suisse, États-Unis
- Massachusetts, Ohio, Victoria (État), Île-de-France
- Melbourne, Paris
- Université Paris-Descartes, Université de Melbourne
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Galbraith Rd., Cincinnati, OH 45237, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A2"> Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea> Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel</wicri:regionArea><wicri:noRegion>4058 Basel</wicri:noRegion></affiliation></author><author><name sortKey="Selvaraj, Anand" sort="Selvaraj, Anand" uniqKey="Selvaraj A" first="Anand" last="Selvaraj">Anand Selvaraj</name><affiliation wicri:level="2"><nlm:aff id="A1"> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A2"> Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea> Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel</wicri:regionArea><wicri:noRegion>4058 Basel</wicri:noRegion></affiliation></author><author><name sortKey="Kim, So Young" sort="Kim, So Young" uniqKey="Kim S" first="So Young" last="Kim">So Young Kim</name><affiliation wicri:level="1"><nlm:aff id="A2"> Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea> Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel</wicri:regionArea><wicri:noRegion>4058 Basel</wicri:noRegion></affiliation><affiliation wicri:level="2"><nlm:aff id="A3"> Dana-Farber Cancer Institute, Department of Medical Oncology 44 Binney Street, D1537, Boston, MA 02115</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea> Dana-Farber Cancer Institute, Department of Medical Oncology 44 Binney Street, D1537, Boston</wicri:cityArea></affiliation></author><author><name sortKey="Gulati, Pawan" sort="Gulati, Pawan" uniqKey="Gulati P" first="Pawan" last="Gulati">Pawan Gulati</name><affiliation wicri:level="2"><nlm:aff id="A1"> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Le, Sophie Br" sort="Le, Sophie Br" uniqKey="Le S" first="Sophie Br" last="Lé">Sophie Br Lé</name><affiliation wicri:level="1"><nlm:aff id="A4"> Department of Anatomy and Physiology & Lipid Research Unit, Laval University Hospital Research Center, Ste-Foy (QC), Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea> Department of Anatomy and Physiology & Lipid Research Unit, Laval University Hospital Research Center, Ste-Foy (QC)</wicri:regionArea><wicri:noRegion>Ste-Foy (QC)</wicri:noRegion></affiliation></author><author><name sortKey="Viollet, Benoit" sort="Viollet, Benoit" uniqKey="Viollet B" first="Benoit" last="Viollet">Benoit Viollet</name><affiliation wicri:level="4"><nlm:aff id="A5"> Institut Cochin, Université Paris Descartes, CNRS, UMR 8104, Paris F-75014, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea> Institut Cochin, Université Paris Descartes, CNRS, UMR 8104, Paris F-75014</wicri:regionArea><wicri:noRegion>75014</wicri:noRegion><placeName><settlement type="city">Paris</settlement><region type="région" nuts="2">Île-de-France</region><settlement type="city">Paris</settlement></placeName><orgName type="university">Université Paris-Descartes</orgName></affiliation><affiliation wicri:level="1"><nlm:aff id="A6">INSERM, U567, Paris-75014, France</nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>INSERM, U567, Paris-75014</wicri:regionArea><wicri:noRegion>75014</wicri:noRegion><wicri:noRegion>75014</wicri:noRegion></affiliation></author><author><name sortKey="Kemp, Bruce" sort="Kemp, Bruce" uniqKey="Kemp B" first="Bruce" last="Kemp">Bruce Kemp</name><affiliation wicri:level="4"><nlm:aff id="A7"> St. Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy, VIC, 3065, Australia</nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea> St. Vincent's Institute of Medical Research, University of Melbourne, 41 Victoria Parade, Fitzroy, VIC, 3065</wicri:regionArea><orgName type="university">Université de Melbourne</orgName><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Bardeesy, Nabeel" sort="Bardeesy, Nabeel" uniqKey="Bardeesy N" first="Nabeel" last="Bardeesy">Nabeel Bardeesy</name><affiliation wicri:level="2"><nlm:aff id="A8"> Massachusetts General Hospital, Center for Cancer Research, Simches Bldg, CPZN 4200, 185 Cambridge Street, Boston, MA 02114</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Massachusetts</region></placeName><wicri:cityArea> Massachusetts General Hospital, Center for Cancer Research, Simches Bldg, CPZN 4200, 185 Cambridge Street, Boston</wicri:cityArea></affiliation></author><author><name sortKey="Dennis, Patrick" sort="Dennis, Patrick" uniqKey="Dennis P" first="Patrick" last="Dennis">Patrick Dennis</name><affiliation wicri:level="2"><nlm:aff id="A1"> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation></author><author><name sortKey="Schlager, John J" sort="Schlager, John J" uniqKey="Schlager J" first="John J." last="Schlager">John J. Schlager</name><affiliation wicri:level="2"><nlm:aff id="A9"> Human Effectiveness Directorate, Air Force Research Laboratory, Wright-Patterson AFB, Dayton OH 45433</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Ohio</region></placeName><wicri:cityArea> Human Effectiveness Directorate, Air Force Research Laboratory, Wright-Patterson AFB</wicri:cityArea></affiliation></author><author><name sortKey="Marette, Andre" sort="Marette, Andre" uniqKey="Marette A" first="André" last="Marette">André Marette</name><affiliation wicri:level="1"><nlm:aff id="A4"> Department of Anatomy and Physiology & Lipid Research Unit, Laval University Hospital Research Center, Ste-Foy (QC), Canada</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea> Department of Anatomy and Physiology & Lipid Research Unit, Laval University Hospital Research Center, Ste-Foy (QC)</wicri:regionArea><wicri:noRegion>Ste-Foy (QC)</wicri:noRegion></affiliation></author><author><name sortKey="Kozma, Sara C" sort="Kozma, Sara C" uniqKey="Kozma S" first="Sara C." last="Kozma">Sara C. Kozma</name><affiliation wicri:level="2"><nlm:aff id="A1"> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A2"> Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea> Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel</wicri:regionArea><wicri:noRegion>4058 Basel</wicri:noRegion></affiliation></author><author><name sortKey="Thomas, George" sort="Thomas, George" uniqKey="Thomas G" first="George" last="Thomas">George Thomas</name><affiliation wicri:level="2"><nlm:aff id="A1"> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea> Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Rd., Cincinnati, OH 45237</wicri:regionArea><placeName><region type="state">Ohio</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="A2"> Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland</nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea> Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel</wicri:regionArea><wicri:noRegion>4058 Basel</wicri:noRegion></affiliation></author></analytic><series><title level="j">Cell metabolism</title><idno type="ISSN">1550-4131</idno><idno type="eISSN">1932-7420</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P1">Dysfunctional mTORC1 signaling is associated with a number of human pathologies owing to its central role in controlling cell growth, proliferation, and metabolism. Regulation of mTORC1 is achieved by the integration of multiple inputs, including those of mitogens, nutrients, and energy. It is thought that agents that increase the cellular AMP/ATP ratio, such as the anti-diabetic biguanides metformin and phenformin, inhibit mTORC1 through AMPK activation of TSC1/2-dependent or -independent mechanisms. Unexpectedly, we found that biguanides inhibit mTORC1 signaling, not only in the absence of TSC1/2, but also in the absence of AMPK. Consistent with these observations, in two distinct pre-clinical models of cancer and diabetes, metformin acts to suppress mTORC1 signaling in an AMPK-independent manner. We found that the ability of biguanides to inhibit mTORC1 activation and signaling is, instead, dependent on the Rag GTPases.</p></div></front></TEI><affiliations><list><country><li>Australie</li><li>Canada</li><li>France</li><li>Suisse</li><li>États-Unis</li></country><region><li>Massachusetts</li><li>Ohio</li><li>Victoria (État)</li><li>Île-de-France</li></region><settlement><li>Melbourne</li><li>Paris</li></settlement><orgName><li>Université Paris-Descartes</li><li>Université de Melbourne</li></orgName></list><tree><country name="États-Unis"><region name="Ohio"><name sortKey="Kalender, Adem" sort="Kalender, Adem" uniqKey="Kalender A" first="Adem" last="Kalender">Adem Kalender</name></region><name sortKey="Bardeesy, Nabeel" sort="Bardeesy, Nabeel" uniqKey="Bardeesy N" first="Nabeel" last="Bardeesy">Nabeel Bardeesy</name><name sortKey="Dennis, Patrick" sort="Dennis, Patrick" uniqKey="Dennis P" first="Patrick" last="Dennis">Patrick Dennis</name><name sortKey="Gulati, Pawan" sort="Gulati, Pawan" uniqKey="Gulati P" first="Pawan" last="Gulati">Pawan Gulati</name><name sortKey="Kim, So Young" sort="Kim, So Young" uniqKey="Kim S" first="So Young" last="Kim">So Young Kim</name><name sortKey="Kozma, Sara C" sort="Kozma, Sara C" uniqKey="Kozma S" first="Sara C." last="Kozma">Sara C. Kozma</name><name sortKey="Schlager, John J" sort="Schlager, John J" uniqKey="Schlager J" first="John J." last="Schlager">John J. Schlager</name><name sortKey="Selvaraj, Anand" sort="Selvaraj, Anand" uniqKey="Selvaraj A" first="Anand" last="Selvaraj">Anand Selvaraj</name><name sortKey="Thomas, George" sort="Thomas, George" uniqKey="Thomas G" first="George" last="Thomas">George Thomas</name></country><country name="Suisse"><noRegion><name sortKey="Kalender, Adem" sort="Kalender, Adem" uniqKey="Kalender A" first="Adem" last="Kalender">Adem Kalender</name></noRegion><name sortKey="Kim, So Young" sort="Kim, So Young" uniqKey="Kim S" first="So Young" last="Kim">So Young Kim</name><name sortKey="Kozma, Sara C" sort="Kozma, Sara C" uniqKey="Kozma S" first="Sara C." last="Kozma">Sara C. Kozma</name><name sortKey="Selvaraj, Anand" sort="Selvaraj, Anand" uniqKey="Selvaraj A" first="Anand" last="Selvaraj">Anand Selvaraj</name><name sortKey="Thomas, George" sort="Thomas, George" uniqKey="Thomas G" first="George" last="Thomas">George Thomas</name></country><country name="Canada"><noRegion><name sortKey="Le, Sophie Br" sort="Le, Sophie Br" uniqKey="Le S" first="Sophie Br" last="Lé">Sophie Br Lé</name></noRegion><name sortKey="Marette, Andre" sort="Marette, Andre" uniqKey="Marette A" first="André" last="Marette">André Marette</name></country><country name="France"><region name="Île-de-France"><name sortKey="Viollet, Benoit" sort="Viollet, Benoit" uniqKey="Viollet B" first="Benoit" last="Viollet">Benoit Viollet</name></region><name sortKey="Viollet, Benoit" sort="Viollet, Benoit" uniqKey="Viollet B" first="Benoit" last="Viollet">Benoit Viollet</name></country><country name="Australie"><region name="Victoria (État)"><name sortKey="Kemp, Bruce" sort="Kemp, Bruce" uniqKey="Kemp B" first="Bruce" last="Kemp">Bruce Kemp</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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