RRC ID 53382
Author Wu L, Zhou B, Oshiro-Rapley N, Li M, Paulo JA, Webster CM, Mou F, Kacergis MC, Talkowski ME, Carr CE, Gygi SP, Zheng B, Soukas AA.
Title An Ancient, Unified Mechanism for Metformin Growth Inhibition in C. elegans and Cancer.
Journal Cell
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.
Volume 167(7)
Pages 1705-1718.e13
Published 2016-12-15
DOI 10.1016/j.cell.2016.11.055
PII S0092-8674(16)31667-1
PMID 27984722
PMC PMC5390486
MeSH Acyl-CoA Dehydrogenase / genetics Aging Animals Body Size Caenorhabditis elegans / growth & development Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Cell Line, Tumor DNA-Binding Proteins / metabolism Humans Longevity Mechanistic Target of Rapamycin Complex 1 Metformin / pharmacology* Mitochondria / metabolism Monomeric GTP-Binding Proteins / metabolism Multiprotein Complexes / metabolism Neoplasms / drug therapy Nuclear Pore / metabolism Oxidative Phosphorylation Signal Transduction / drug effects TOR Serine-Threonine Kinases / metabolism Transcription Factors / metabolism
IF 38.637
Times Cited 82
C.elegans tm1944