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Distinct perturbation of the translatome by the anti-diabetic drug metformin

ABSTRACT: Reduced cancer incidence has been reported among type II diabetics treated with metformin. Metformin exhibits anti-proliferative and anti-neoplastic effects associated with inhibition of mTORC1, but the mechanisms are poorly understood. We provide the first genome-wide analysis of translational targets of canonical mTOR inhibitors (rapamycin and PP242) and metformin, revealing that metformin controls gene expression at the level of mRNA translation to an extent comparable to that of canonical mTOR inhibitors. Importantly, metformin's anti-proliferative activity can be explained by selective translational suppression of mRNAs encoding cell cycle regulators via the mTORC1/4E-BP pathway. Thus, metformin selectively inhibits mRNA translation of encoded proteins that promote neoplastic proliferation, motivating further studies of this compound and related biguanides in cancer prevention and treatment. MCF7 cells were treated with rapamycin, metformin or PP242 at concentrations that inhibited proliferation to 50% of control. Both cytoplasmic and polysome-associated mRNA was extracted from treatments and a vehicle treated control and probed with microarrays.

ORGANISM(S): Homo sapiens

SUBMITTER: Ola Larsson

PROVIDER: E-GEOD-36847 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Distinct perturbation of the translatome by the anti-diabetic drug metformin

Project description:Reduced cancer incidence has been reported among type II diabetics treated with metformin. Metformin exhibits anti-proliferative and anti-neoplastic effects associated with inhibition of mTORC1, but the mechanisms are poorly understood. We provide the first genome-wide analysis of translational targets of canonical mTOR inhibitors (rapamycin and PP242) and metformin, revealing that metformin controls gene expression at the level of mRNA translation to an extent comparable to that of canonical mTOR inhibitors. Importantly, metformin's anti-proliferative activity can be explained by selective translational suppression of mRNAs encoding cell cycle regulators via the mTORC1/4E-BP pathway. Thus, metformin selectively inhibits mRNA translation of encoded proteins that promote neoplastic proliferation, motivating further studies of this compound and related biguanides in cancer prevention and treatment.

2012-05-21 | GSE36847 | GEO

Transcriptional profiling of ATP-competitive mTOR inhibitors reveals mTORC1 and mTORC2 specific regulatory networks

Project description:The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation in response to growth factor and nutrient signaling. Consequently, this kinase is implicated in metabolic diseases including cancer and diabetes so there is great interest in understanding mTOR regulatory networks. mTOR exists in two functionally distinct complexes, mTORC1 and mTORC2, and whereas the natural product rapamycin only inhibits a subset of mTORC1 functions, recently developed ATP-competitive mTOR inhibitors have revealed new roles for both complexes. To examine the complete spectrum of mTOR responsive cellular processes, we compared the transcriptional profiles of mammalian cells treated with rapamycin versus the ATP-competitive inhibitor PP242. Our analysis provides a genome-wide view of the transcriptional outputs of mTOR signaling that are insensitive to rapamycin. Gene expression in mouse NIH3T3 cells was measured after 18 hour treatment with DMSO (control), 50 nM rapamycin, or 2 uM PP242. Four independent experiments were performed for each condition.

2011-03-15 | E-GEOD-27784 | biostudies-arrayexpress

screen miRNAs specifically regulated by mTORC1 or mTORC2

Project description:To screen miRNAs specifically regulated by mTORC1 or mTORC2, a global miRNA expression profile in MCF-7 cells treated with rapamycin or PP242 (mTORC1/2 kinase inhibitor) was developed using microarray. control, rapamycin or PP242 treated human MCF-7 cells were harvested 48h post-treatment and subjected to total RNA extraction.

2014-09-11 | E-GEOD-61289 | biostudies-arrayexpress

Transcriptional profiling of ATP-competitive mTOR inhibitors reveals mTORC1 and mTORC2 specific regulatory networks

2011-03-15 | GSE27784 | GEO

screen miRNAs specifically regulated by mTORC1 or mTORC2

2014-09-11 | GSE61289 | GEO

mTORC1 and -2 Coordinate Transcriptional and Translational Reprogramming in Resistance to DNA Damage and Replicative Stress in Breast Cancer Cells

Project description:mTOR coordinates growth signals with metabolic pathways and protein synthesis and is hyperactivated in many human cancers. We have characterized the coordinated mTORC1 and -2 transcription and translation response using genome-wide translatome and transcriptome profiling on cells inhibited in mTORC1/2 with PP242 or only mTORC1 with RAD001, with or without concurrent IR. In this dataset, we include the expression data obtained from SUM149 cells treated with RAD001 + IR, RAD001, PP242+IR, PP242, IR, DMSO. We include both total (transcriptional) data as well as polysome arrays. These data are used to obtain differentially expressed genes in all treatments compared to DMSO in both polysome and transcriptional data.

2016-12-20 | GSE92598 | GEO

Transcription profiling by array of mouse immortalized embryonic fibroblasts to identify genes regulated by mTORC1

Project description:Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a critical regulator of cell growth by integrating multiple signals (nutrients, growth factors, energy and stress) and is frequently deregulated in many types of cancer. We used a robust experimental paradigm involving the combination of two interventions, one genetic and one pharmacologic to identify genes regulated transcriptionally by mTORC1. In Tsc2+/+, but not Tsc2-/- immortalized mouse embryo fibroblasts (MEFs), serum deprivation downregulates mTORC1 activity. In Tsc2-/- cells, abnormal mTORC1 activity can be downregulated by treatment with rapamycin (sirolimus). By contrast, rapamycin has little effect on mTORC1 in Tsc2+/+ cells in which mTORC1 is already inhibited by low serum. Thus, under serum deprived conditions, mTORC1 activity is low in Tsc2+/+ cells (untreated or rapamycin treated), high in Tsc2-/- cells, but lowered by rapamycin; a pattern referred to as a M-^Slow/low/high/lowM-^T or M-^SLLHLM-^T, which allowed the identification of genes regulated by mTORC1 by performing the appropriate comparisons

2011-08-02 | E-GEOD-27982 | biostudies-arrayexpress

Selective Inhibitors of mTORC1 Activate 4EBP1 and Suppress Tumor Growth

Project description:The clinical benefit of current mTOR inhibitors is limited, perhaps reflecting their intrinsic pharmacological profiles. Rapamycin analogs selectively inhibit mTORC1, but fail to suppress phosphorylation of the mTORC1 substrate 4EBP1, a translational repressor that is a key driver of oncogenic mTORC1 signaling. mTOR kinase active-site inhibitors fully suppress mTORC1 and phosphorylation of its substrates, but are active against mTORC2 and additional kinases, potentially contributing to tolerability limitations. The prototype bi-steric inhibitor RapaLink-1 exploits the selective mTORC1 interactions of rapamycin and the broad mTOR kinase inhibitory effects of an active-site inhibitor, through covalent linkage of the two pharmacophores to achieve complete mTORC1/2 inhibition. We demonstrate that the anti-proliferative activity of RapaLink-1 is dependent upon mTORC1 and suppression of 4EBP1 phosphorylation. Using a rational design strategy, we tuned the affinities of the rapamycin core and ATP-mimetic moieties to create novel bi-steric inhibitors with enhanced mTORC1 selectivity and potency against 4EBP1 phosphorylation. mTORC1-selective bi-steric compounds produced durable inhibition of 4EBP1 phosphorylation in vitro and in vivo, and drove tumor regressions at well-tolerated doses in xenograft models of breast cancer.

2021-04-05 | GSE138417 | GEO

Dorvash2019 - Dynamic modeling of signal transduction by mTOR complexes in cancer

Project description:This model is based on: Dynamic modeling of signal transduction by mTOR complexes in cancer Author: Mohammadreza Dorvash, Mohammad Farahmandnia, Pouria Mosaddeghi, Mitra Farahmandnejad, Hosein Saber, Mohammadhossein Khorraminejad-Shirazi, Amir Azadi, Iman Tavassoly Abstract: Signal integration has a crucial role in the cell fate decision and dysregulation of the cellular signaling pathways is a primary characteristic of cancer. As a signal integrator, mTOR shows a complex dynamical behavior which determines the cell fate at different cellular processes levels, including cell cycle progression, cell survival, cell death, metabolic reprogramming, and aging. The dynamics of the complex responses to rapamycin in cancer cells have been attributed to its differential time-dependent inhibitory effects on mTORC1 and mTORC2, the two main complexes of mTOR. Two explanations were previously provided for this phenomenon: 1-Rapamycin does not inhibit mTORC2 directly, whereas it prevents mTORC2 formation by sequestering free mTOR protein (Le Chatelier’s principle). 2-Components like Phosphatidic Acid (PA) further stabilize mTORC2 compared with mTORC1. To understand the mechanism by which rapamycin differentially inhibits the mTOR complexes in the cancer cells, we present a mathematical model of rapamycin mode of action based on the first explanation, i.e., Le Chatelier’s principle. Translating the interactions among components of mTORC1 and mTORC2 into a mathematical model revealed the dynamics of rapamycin action in different doses and time-intervals of rapamycin treatment. This model shows that rapamycin has stronger effects on mTORC1 compared with mTORC2, simply due to its direct interaction with free mTOR and mTORC1, but not mTORC2, without the need to consider other components that might further stabilize mTORC2. Based on our results, even when mTORC2 is less stable compared with mTORC1, it can be less inhibited by rapamycin.

2024-09-02 | BIOMD0000000822 | BioModels

Therapeutic interference with mTorc1 restricts inflammation-associated and Stat3-dependent gastro-intestinal tumourigenesis in mice

Project description:Gp130 receptor engagement on neoplastic cells provides a link by which an inflammatory microenvironment facilitates tumour promotion. Although hyperactivation of the gp130-dependent Stat3 signalling node is commonly observed in solid tumours, Stat3 remains a challenging therapeutic target. To mimic excessive Stat3 signalling, we molecularly validate the gp130FF mouse as a preclinical model for inflammation-associated intestinal-type gastric cancer (IGC), with aberrant mammalian target of rapamycin (mTOR) pathway activity as shared feature. Accordingly, administration of the mTorc1 inhibitor RAD001 reversibly reduced IGC burden in gp130FF mice and suppressed colitis-associated cancer in wild-type mice. Since the therapeutic effect of RAD001 occurs independently of Stat3 hyperactivation, which is also dispensable for gp130-dependent engagement of the PI3K/Akt/mTorc1 pathway, we conclude that mTorc1 signalling limits tumour promoting Stat3 activity The mouse whole-genome gene expression profiling was performed on Illumina's MouseWG-6 v2.0 Expression BeadChips for 24 mice, with 8 mice in each group (gp130WT antral tissue, gp130FF unaffected antral tissue and gp130FF tumour tissue).

2013-01-29 | E-GEOD-35808 | biostudies-arrayexpress

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