title: An Ancient, Unified Mechanism for Metformin Growth Inhibition in C. elegans and Cancer.
abstract: Metformin has utility in cancer prevention and treatment, though the mechanisms for these effects remain elusive. Through genetic screening in C. elegans, we uncover two metformin response elements: the nuclear pore complex (NPC) and acyl-CoA dehydrogenase family member-10 (ACAD10). We demonstrate that biguanides inhibit growth by inhibiting mitochondrial respiratory capacity, which restrains transit of the RagA-RagC GTPase heterodimer through the NPC. Nuclear exclusion renders RagC incapable of gaining the GDP-bound state necessary to stimulate mTORC1. Biguanide-induced inactivation of mTORC1 subsequently inhibits growth through transcriptional induction of ACAD10. This ancient metformin response pathway is conserved from worms to humans. Both restricted nuclear pore transit and upregulation of ACAD10 are required for biguanides to reduce viability in melanoma and pancreatic cancer cells, and to extend C. elegans lifespan. This pathway provides a unified mechanism by which metformin kills cancer cells and extends lifespan, and illuminates potential cancer targets. PAPERCLIP.
authors.affiliation: Department of Medicine, Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Medicine, Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Noriko
authors.initials: N
authors.lastname: Oshiro-Rapley
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Joao A
authors.initials: JA
authors.lastname: Paulo
authors.affiliation: Department of Medicine, Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Webster
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Mou
authors.affiliation: Department of Medicine, Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Kacergis
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Talkowski
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Earth, Atmospheric and Planetary Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Carr
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Department of Medicine, Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: asoukas@mgh.harvard.edu.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Soukas
mesh_terms: D042964:Acyl-CoA Dehydrogenase / Q000235:genetics; D000375:Aging; D000818:Animals; D049628:Body Size; D017173:Caenorhabditis elegans / Q000254:growth & development / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D008136:Longevity; D000076222:Mechanistic Target of Rapamycin Complex 1; D008687:Metformin / Q000494:pharmacology*; D008928:Mitochondria / Q000378:metabolism; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy; D022022:Nuclear Pore / Q000378:metabolism; D010085:Oxidative Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; D014157:Transcription Factors; C073702:skn-1 protein, C elegans; D008687:Metformin; C000618373:ACAD-10 protein, C elegans; D042964:Acyl-CoA Dehydrogenase; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins
keywords: ACAD10; C. elegans; Metformin; NPC; RagC GTPase; acyl-CoA dehydrogenase family member 10; cancer; diabetes; growth; lifespan; mTORC1; mechanistic target of rapamycin complex 1; mitochondrial respiratory capacity; nuclear pore complex; nuclear transport