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An Ancient, Unified Mechanism for Metformin Growth Inhibition in C. elegans and Cancer.

Cell | Dec 15, 2016

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.

Pubmed ID: 27984722 RIS Download

Mesh terms: Acyl-CoA Dehydrogenase | Aging | Animals | Body Size | Caenorhabditis elegans | Caenorhabditis elegans Proteins | Cell Line, Tumor | DNA-Binding Proteins | Humans | Longevity | Mechanistic Target of Rapamycin Complex 1 | Metformin | Mitochondria | Monomeric GTP-Binding Proteins | Multiprotein Complexes | Neoplasms | Nuclear Pore | Oxidative Phosphorylation | Signal Transduction | TOR Serine-Threonine Kinases | Transcription Factors

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Associated grants

  • Agency: NIDDK NIH HHS, Id: R01 DK101522
  • Agency: NIDDK NIH HHS, Id: P30 DK040561
  • Agency: NIDDK NIH HHS, Id: R03 DK098436
  • Agency: NIH HHS, Id: P40 OD010440
  • Agency: NIDDK NIH HHS, Id: K08 DK087941
  • Agency: NIDDK NIH HHS, Id: R01 DK072041
  • Agency: NIDDK NIH HHS, Id: K01 DK098285
  • Agency: NCI NIH HHS, Id: R01 CA166717
  • Agency: NIDDK NIH HHS, Id: P30 DK057521

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Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.

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