Dataset Information

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.

SUBMITTER: Wu L

PROVIDER: S-EPMC5390486 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Wu Lianfeng L Zhou Ben B Oshiro-Rapley Noriko N Li Man M Paulo Joao A JA Webster Christopher M CM Mou Fan F Kacergis Michael C MC Talkowski Michael E ME Carr Christopher E CE Gygi Steven P SP Zheng Bin B Soukas Alexander A AA

Cell 20161201 7

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 ...[more]

PMID: 27984722

Similar Datasets

Project description:Background:Compound adduct is a eutectic crystal formed by non-covalent bonds of two compounds or multiple compounds with water. Emerging evidence suggests that adduct could be different from the simple physical mixture of the individual compounds and has some new features. Recent studies reported that both glimepiride (Gli) and metformin (Met) may possess an anti-breast cancer effect besides anti-diabetic effect. In the current study, we synthesized glimepiride-metformin adduct (GMA) and examined its anti-breast cancer effect in vitro and in vivo to explore its potential in treatment of breast cancer in diabetic patients. Methods:GMA was synthesized from Gli, Met and water at a molar molecular mass of 1:1:1 and identified by infrared spectroscopy. MTT assay, colony formation assay and wound healing assay were performed to examine the effects of GMA on cell viability and migration of human breast cancer cell lines CAL-148, MDA-MB-453, MDA-MB-231and MCF-7. The effect of GMA on cell cycle and apoptosis was examined by flow cytometry. The orthotopic implantation model was established to observe the inhibitory effect of GMA on tumor growth. The expression of Ki67 was detected by immunohistochemistry. RT-qPCR and Western blotting were performed to investigate mechanisms for the function of GMA. Results:Both MTT and colony formation assays showed that GMA inhibited breast cancer cell viability, and the effect was greater than Gli alone, Met alone and the combination. In vivo study showed that GMA had an inhibitory effect on tumor growth of CAL-148 xenografts. Flow cytometry analysis indicated that GMA induced G1/S phase cell cycle arrest and apoptosis in breast cancer cells. RT-qPCR and Western blotting analyses showed that GMA activated AMPK, and up-regulated expression of p53 and p21, and down-regulated expression of cyclin D1 and CDK4. Conclusion:GMA suppresses cell viability of breast cancer cells, and its effect is greater than Gli and Met alone or combination at the same concentration. GMA inhibits breast cancer cell growth in vivo. The antitumor effect of GMA may be related to the activation of AMPK resulting in up-regulation of p53 and p21 and down-regulation of cyclin D1 and CDK4.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets