scholarly journals Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Anthony J Covarrubias ◽  
Halil Ibrahim Aksoylar ◽  
Jiujiu Yu ◽  
Nathaniel W Snyder ◽  
Andrew J Worth ◽  
...  
Keyword(s):  
Histone Acetylation ◽  
Macrophage Activation ◽  
Cellular Proliferation ◽  
Gene Induction ◽  
Metabolic State ◽  
Chemokine Production ◽  
Mtorc1 Signaling ◽  
Key Enzyme ◽  
Mtorc1 Pathway ◽  
Functional States

Macrophage activation/polarization to distinct functional states is critically supported by metabolic shifts. How polarizing signals coordinate metabolic and functional reprogramming, and the potential implications for control of macrophage activation, remains poorly understood. Here we show that IL-4 signaling co-opts the Akt-mTORC1 pathway to regulate Acly, a key enzyme in Ac-CoA synthesis, leading to increased histone acetylation and M2 gene induction. Only a subset of M2 genes is controlled in this way, including those regulating cellular proliferation and chemokine production. Moreover, metabolic signals impinge on the Akt-mTORC1 axis for such control of M2 activation. We propose that Akt-mTORC1 signaling calibrates metabolic state to energetically demanding aspects of M2 activation, which may define a new role for metabolism in supporting macrophage activation.

scholarly journals Modulation of mTORC1 Signaling Pathway by HIV-1

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1090 ◽  
Author(s):  
Burkitkan Akbay ◽  
Anna Shmakova ◽  
Yegor Vassetzky ◽  
Svetlana Dokudovskaya
Keyword(s):  
Cellular Response ◽  
Cellular Proliferation ◽  
Mammalian Target Of Rapamycin ◽  
Host Cells ◽  
Promising Strategy ◽  
Mtorc1 Signaling ◽  
Mtorc1 Pathway ◽  
Recent Trends ◽  
Hiv 1

Mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cellular proliferation and survival which controls cellular response to different stresses, including viral infection. HIV-1 interferes with the mTORC1 pathway at every stage of infection. At the same time, the host cells rely on the mTORC1 pathway and autophagy to fight against virus replication and transmission. In this review, we will provide the most up-to-date picture of the role of the mTORC1 pathway in the HIV-1 life cycle, latency and HIV-related diseases. We will also provide an overview of recent trends in the targeting of the mTORC1 pathway as a promising strategy for HIV-1 eradication.

scholarly journals Prostaglandin E2 activates the mTORC1 pathway through an EP4/cAMP/PKA- and EP1/Ca2+-mediated mechanism in the human pancreatic carcinoma cell line PANC-1

2015 ◽  
Vol 309 (10) ◽  
pp. C639-C649 ◽  
Author(s):  
Hui-Hua Chang ◽  
Steven H. Young ◽  
James Sinnett-Smith ◽  
Caroline Ei Ne Chou ◽  
Aune Moro ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Pancreatic Cancer ◽  
Prostaglandin E2 ◽  
Human Pancreatic Cancer ◽  
Pancreatic Carcinoma Cell Line ◽  
Pancreatic Cancer Cells ◽  
Mtorc1 Signaling ◽  
Mtorc1 Pathway ◽  
Pka Pathway ◽  
Mtorc1 Activation

Obesity, a known risk factor for pancreatic cancer, is associated with inflammation and insulin resistance. Proinflammatory prostaglandin E2 (PGE2) and elevated insulin-like growth factor type 1 (IGF-1), related to insulin resistance, are shown to play critical roles in pancreatic cancer progression. We aimed to explore a potential cross talk between PGE2 signaling and the IGF-1/Akt/mammalian target of rapamycin complex 1 (mTORC1) pathway in pancreatic cancer, which may be a key to unraveling the obesity-cancer link. In PANC-1 human pancreatic cancer cells, we showed that PGE2 stimulated mTORC1 activity independently of Akt, as evaluated by downstream signaling events. Subsequently, using pharmacological and genetic approaches, we demonstrated that PGE2-induced mTORC1 activation is mediated by the EP4/cAMP/PKA pathway, as well as an EP1/Ca2+-dependent pathway. The cooperative roles of the two pathways were supported by the maximal inhibition achieved with the combined pharmacological blockade, and the coexistence of highly expressed EP1 (mediating the Ca2+ response) and EP2 or EP4 (mediating the cAMP/PKA pathway) in PANC-1 cells and in the prostate cancer line PC-3, which also robustly exhibited PGE2-induced mTORC1 activation, as identified from a screen in various cancer cell lines. Importantly, we showed a reinforcing interaction between PGE2 and IGF-1 on mTORC1 signaling, with an increase in IL-23 production as a cellular outcome. Our data reveal a previously unrecognized mechanism of PGE2-stimulated mTORC1 activation mediated by EP4/cAMP/PKA and EP1/Ca2+ signaling, which may be of great importance in elucidating the promoting effects of obesity in pancreatic cancer. Ultimately, a precise understanding of these molecular links may provide novel targets for efficacious interventions devoid of adverse effects.

Induction of autophagy across multiple tumor types through irreversible HER tyrosine kinase blockade.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13517-e13517
Author(s):  
William Rayford Gwin ◽  
Leihua Liu ◽  
Sumin Zhao ◽  
Wenle Xia ◽  
Neil Spector
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Cellular Proliferation ◽  
Kinase Inhibitor ◽  
Significant Inhibition ◽  
Wild Type ◽  
Multiple Tumor ◽  
Mtorc1 Signaling

e13517 Background: Human epidermal growth factor receptor (HER) receptor tyrosine kinases play a key role in solid tumor oncogenesis. Despite broad expression of HER receptors in solid tumors, HER targeted therapies have not shown significant improvement in survival, calling into question the value of wild-type HER receptors as therapeutic targets. Here we found that an irreversible pan-HER tyrosine kinase inhibitor (TKI), neratinib, but not similar HER TKIs, induced morphologic changes in ovarian, TNBC, and prostate cancer cell lines consistent with induction of autophagy. Methods: SKOV3 (ovarian), OVCAR8 (ovarian), HBL-100 (TNBC), and LAPC4 (prostate) cancer cells were treated with lapatinib, gefitinib, CI-1033, afatinib, and neratinib (0.5mM-2.5mM). The activation state of HER2, EGFR, HER3, Akt, Erk, p70S6, 4EBP1, and Ulk1 was determined by Western blot analysis (WB) at various time points of neratinib treatment. LC3 was analyzed by immunofluorescence (IF) microscopy and WB. Analysis of proliferation, apoptosis, and cell cycle were performed using WST-1, annexin V, and PI staining, respectively. Results: Neratinib, but not similar HER TKIs, induced marked cytoplasmic vacuolization in tumors. The conversion of LC3-I to LC3-II in neratinib-treated cells was consistent with induction of autophagy. Moreover, PI3K/Akt, MAPK/Erk1/2 and mTORC1 signaling cascades were inhibited in neratinib-treated cells, and were associated with the inhibition of phospho-Ulk1, a key step in autophagy initiation. Treatment with neratinib alone resulted in G1 cell cycle arrest. Importantly, the combination of neratinib and chloroquine, an autophagy inhibitor, induced a statistically significant inhibition of cellular proliferation (p <0.01) and increased apoptosis compared to treatment with either drug alone. Conclusions: Our data suggest that more effective inhibition of wild-type HER receptors, can lead to mTORC1 inhibition, which in turn triggers autophagy. Here, autophagy appears to protect cells rather than inducing apoptosis. Consequently, targeting both HER receptors and autophagy represents an attractive therapeutic strategy to treat tumors expressing wild-type HER receptors.

scholarly journals IL-2– and IL-15–induced activation of the rapamycin-sensitive mTORC1 pathway in malignant CD4+ T lymphocytes

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2181-2189 ◽  
Author(s):  
Michal Marzec ◽  
Xiaobin Liu ◽  
Monika Kasprzycka ◽  
Agnieszka Witkiewicz ◽  
Puthiyaveettil N. Raghunath ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lines ◽  
Cell Transformation ◽  
Single Agent ◽  
Large Cell ◽  
Dependent Manner ◽  
T Cell Lymphomas ◽  
Mtorc1 Signaling ◽  
Mtorc1 Pathway ◽  
Mtorc1 Activation

We examined functional status, activation mechanisms, and biologic role of the mTORC1 signaling pathway in malignant CD4+ T cells derived from the cutaneous T-cell lymphoma (CTCL). Whereas the spontaneously growing CTCL-derived cell lines displayed persistent activation of the TORC1 as well as the PI3K/Akt and MEK/ERK pathways, the IL-2–dependent cell lines activated the pathways in response to IL-2 and IL-15 but not IL-21. Activation of mTORC1 and MEK/ERK was nutrient dependent. The mTORC1, PI3K/Akt, and MEK/ERK pathways could also be activated by IL-2 in the primary leukemic, mitogen-preactivated CTCL cells. mTORC1 activation was also detected in the CTCL tissues in the lymphoma stage–dependent manner with the highest percentage of positive cells present in the cases with a large cell transformation. Rapamycin inhibited mTORC1 signaling and suppressed CTCL cell proliferation but showed little effect on their apoptotic rate when used as a single agent. Activation of the mTORC1, PI3K/Akt, and MEK/ERK pathways was strictly dependent on the Jak3 and Jak1 kinases. Finally, mTORC1 activation was transduced preferentially through the PI3K/Akt pathway. These findings document the selective γc-signaling cytokine-mediated activation of the mTORC1 pathway in the CTCL cells and suggest that the pathway represents a therapeutic target in CTCL and, possibly, other T-cell lymphomas.

scholarly journals miR-548d-3p Alters Parasite Growth and Inflammation in Leishmania (Viannia) braziliensis Infection

2021 ◽  
Vol 11 ◽  
Author(s):  
Marina de Assis Souza ◽  
Eduardo Milton Ramos-Sanchez ◽  
Sandra Márcia Muxel ◽  
Dimitris Lagos ◽  
Luiza Campos Reis ◽  
...  
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Cellular Proliferation ◽  
Clinical Manifestations ◽  
Target Prediction ◽  
Parasite Growth ◽  
Healthy Controls ◽  
Chemokine Production ◽  
Chemokine Signaling ◽  
American Tegumentary Leishmaniasis

American Tegumentary Leishmaniasis (ATL) is an endemic disease in Latin America, mainly caused in Brazil by Leishmania (Viannia) braziliensis. Clinical manifestations vary from mild, localized cutaneous leishmaniasis (CL) to aggressive mucosal disease. The host immune response strongly determines the outcome of infection and pattern of disease. However, the pathogenesis of ATL is not well understood, and host microRNAs (miRNAs) may have a role in this context. In the present study, miRNAs were quantified using qPCR arrays in human monocytic THP-1 cells infected in vitro with L. (V.) braziliensis promastigotes and in plasma from patients with ATL, focusing on inflammatory response-specific miRNAs. Patients with active or self-healed cutaneous leishmaniasis patients, with confirmed parasitological or immunological diagnosis, were compared with healthy controls. Computational target prediction of significantly-altered miRNAs from in vitro L. (V.) braziliensis-infected THP-1 cells revealed predicted targets involved in diverse pathways, including chemokine signaling, inflammatory, cellular proliferation, and tissue repair processes. In plasma, we observed distinct miRNA expression in patients with self-healed and active lesions compared with healthy controls. Some miRNAs dysregulated during THP-1 in vitro infection were also found in plasma from self-healed patients, including miR-548d-3p, which was upregulated in infected THP-1 cells and in plasma from self-healed patients. As miR-548d-3p was predicted to target the chemokine pathway and inflammation is a central to the pathogenesis of ATL, we evaluated the effect of transient transfection of a miR-548d-3p inhibitor on L. (V.) braziliensis infected-THP-1 cells. Inhibition of miR-548d-3p reduced parasite growth early after infection and increased production of MCP1/CCL2, RANTES/CCL5, and IP10/CXCL10. In plasma of self-healed patients, MCP1/CCL2, RANTES/CCL5, and IL-8/CXCL8 concentrations were significantly decreased and MIG/CXCL9 and IP-10/CXCL10 increased compared to patients with active disease. These data suggest that by modulating miRNAs, L. (V.) braziliensis may interfere with chemokine production and hence the inflammatory processes underpinning lesion resolution. Our data suggest miR-548d-3p could be further evaluated as a prognostic marker for ATL and/or as a host-directed therapeutic target.

scholarly journals Genome-wide CRISPR screens reveal multitiered mechanisms through which mTORC1 senses mitochondrial dysfunction

2021 ◽  
Vol 118 (4) ◽  
pp. e2022120118
Author(s):  
Kendall J. Condon ◽  
Jose M. Orozco ◽  
Charles H. Adelmann ◽  
Jessica B. Spinelli ◽  
Pim W. van der Helm ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mammalian Cells ◽  
Growth Control ◽  
Screening Strategy ◽  
Genome Wide ◽  
Mtorc1 Signaling ◽  
Full Complement ◽  
Mtorc1 Pathway ◽  
Synthase Inhibitor ◽  
Almost All

In mammalian cells, nutrients and growth factors signal through an array of upstream proteins to regulate the mTORC1 growth control pathway. Because the full complement of these proteins has not been systematically identified, we developed a FACS-based CRISPR-Cas9 genetic screening strategy to pinpoint genes that regulate mTORC1 activity. Along with almost all known positive components of the mTORC1 pathway, we identified many genes that impact mTORC1 activity, including DCAF7, CSNK2B, SRSF2, IRS4, CCDC43, and HSD17B10. Using the genome-wide screening data, we generated a focused sublibrary containing single guide RNAs (sgRNAs) targeting hundreds of genes and carried out epistasis screens in cells lacking nutrient- and stress-responsive mTORC1 modulators, including GATOR1, AMPK, GCN2, and ATF4. From these data, we pinpointed mitochondrial function as a particularly important input into mTORC1 signaling. While it is well appreciated that mitochondria signal to mTORC1, the mechanisms are not completely clear. We find that the kinases AMPK and HRI signal, with varying kinetics, mitochondrial distress to mTORC1, and that HRI acts through the ATF4-dependent up-regulation of both Sestrin2 and Redd1. Loss of both AMPK and HRI is sufficient to render mTORC1 signaling largely resistant to mitochondrial dysfunction induced by the ATP synthase inhibitor oligomycin as well as the electron transport chain inhibitors piericidin and antimycin. Taken together, our data reveal a catalog of genes that impact the mTORC1 pathway and clarify the multifaceted ways in which mTORC1 senses mitochondrial dysfunction.

scholarly journals Author response: Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation

2015 ◽  
Author(s):  
Anthony J Covarrubias ◽  
Halil Ibrahim Aksoylar ◽  
Jiujiu Yu ◽  
Nathaniel W Snyder ◽  
Andrew J Worth ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Author Response ◽  
Mtorc1 Signaling

scholarly journals circRNA LDLRAD3 Enhances the Malignant Behaviors of NSCLC Cells via the miR-20a-5p-SLC7A5 Axis Activating the mTORC1 Signaling Pathway

2022 ◽  
Vol 2022 ◽  
pp. 1-10
Author(s):  
Yu Li ◽  
Guangle Qin ◽  
Jinyun Du ◽  
Peng Yue ◽  
Yanling Zhang ◽  
...  
Keyword(s):  
Western Blot ◽  
Signaling Pathway ◽  
Circular Rna ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Potential Therapeutic Target ◽  
Expression Levels ◽  
Mtorc1 Signaling ◽  
Mtorc1 Pathway ◽  
Related Proteins

Circular RNA LDLRAD3 behaved as an oncogene in several malignancies, but its effects in NSCLC and the involvement of downstream molecules and activation of signaling pathways had not been fully reported. We planned to explore how LDLRAD3 facilitated the malignancy of NSCLC. QRT-PCR was performed to evaluate the expression levels of LDLRAD3, miR-20a-5p, and SLC7A5 in NSCLC tissues and cells. si-LDLRAD3 was transfected to A549 and H1299 cells to knock down intrinsic LDLRAD3 to determine its oncogenic roles. CCK-8 assay and transwell assay were executed to assess cell proliferative, migrative, and invasive abilities. Dual-luciferase reporter (DLR) assay was manipulated to verify the ENCORI-predicted relationships between LDLRAD3 and miR-20a-5p and between miR-20a-5p and SLC7A5. Western blot, immunofluorescent assay, and immunohistochemistry were applied to explore the expression levels of SLC7A5, and the levels of mTORC1 pathway-related proteins were evaluated using western blot. Rescue experiments were conducted by transfecting si-LDLRAD3, miR-20a-5p inhibitor, and si-SLC7A5 to explore the influence of the LDLRAD3-miR-20a-5p-SLC7A5 axis on the malignant behaviors of NSCLC cells. The expression levels of LDLRAD3 and SLC7A5 were boosted, whereas miR-20a-5p was impeded in NSCLC tissues and cell lines. Knockdown of LDLRAD3 weakened the proliferation, migration, and invasion of A549 and H1299 cells. LDLRAD3 was verified to sponge miR-20a-5p and miR-20a-5p targeted SLC7A5. LDLRAD3 activated the mTORC1 singling pathway via the miR-20a-5p-SLC7A5 axis to strengthen the malignant properties of A549 and H1299 cells. We concluded that LDLRAD3 exerted oncogenic effects via the miR-20a-5p-SLC7A5 axis to activate the mTORC1 signaling pathway in NSCLC. Our findings enlightened that LDLRAD3 could become a potential therapeutic target in the treatment and management of NSCLC.

scholarly journals Galectin-3 Is a Potential Mediator for Atherosclerosis

2020 ◽  
Vol 2020 ◽  
pp. 1-11 ◽  
Author(s):  
Ziyu Gao ◽  
Zhongni Liu ◽  
Rui Wang ◽  
Yinghong Zheng ◽  
Hong Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Macrophage Activation ◽  
Cellular Proliferation ◽  
Arterial Disease ◽  
Inflammatory Factor ◽  
Potential Mediator ◽  
Galectin 3 ◽  
Monocyte Chemotaxis ◽  
Progression Of Atherosclerosis

Atherosclerosis is a multifactorial chronic inflammatory arterial disease forming the pathological basis of many cardiovascular diseases such as coronary heart disease, heart failure, and stroke. Numerous studies have implicated inflammation as a key player in the initiation and progression of atherosclerosis. Galectin-3 (Gal-3) is a 30 kDa β-galactose, highly conserved and widely distributed intracellularly and extracellularly. Gal-3 has been demonstrated in recent years to be a novel inflammatory factor participating in the process of intravascular inflammation, lipid endocytosis, macrophage activation, cellular proliferation, monocyte chemotaxis, and cell adhesion. This review focuses on the role of Gal-3 in atherosclerosis and the mechanism involved and several classical Gal-3 agonists and antagonists in the current studies.

Abstract P446: Sestrin2 Suppresses Age-related Hypertrophy by Inhibiting mTORC1 Signaling Pathway

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Nanhu Quan ◽  
Courtney Cates ◽  
Thomas Rousselle ◽  
Ji Li
Keyword(s):  
Ex Vivo ◽  
Energy State ◽  
Critical Role ◽  
Pressure Overload ◽  
Acid Oxidation ◽  
Protein Levels ◽  
Age Related ◽  
Mtorc1 Signaling ◽  
Mtorc1 Pathway ◽  
Mtorc1 Activation

Introduction: The mechanistic target of rapamycin complex 1 (mTORC1) plays a critical role in the regulation of cell growth and energy state. A novel stress-inducible protein, Sestrin2 was recognized as a sensor for mTORC1 pathway. Hypothesis: The cardiac mTORC1 activation modulated by Sestrin2 is impaired in aging that sensitizes heart to hypertrophy. Methods: C57BL/6J young WT (4-6 months) and aged WT mice (24-26 months), and young Sestrin2 knockout mice (4-6 months) were subjected to transverse aortic constriction (TAC) for pressure overload. The ex vivo working heart perfusion was used for measuring substrate metabolism. Results: The protein levels of cardiac Sestrin2 were decreased with aging. There are no phenotypic differences in young WT, aged WT and Sesn2 KO mice under normal physiology, while aged WT and Sesn2 KO versus young WT mice exhibit bigger hearts after 4 weeks of TAC surgery. The echocardiography showed an impaired cardiac function of aged WT and Sesn2 KO hearts by pressure overload. The pressure overload-induced phosphorylation of mTOR and mTORC1 downstream effectors 4E-BP1 and p70S6K were augmented in aged WT and Sesn2 KO versus young WT hearts. The swollen mitochondria with severely disrupted cristae and higher levels of redox markers pShc 66 and 4-hydroxynonenal were observed in aged WT and Sesn2 KO versus young WT hearts by pressure overload. The rate of glucose oxidation and fatty acid oxidation were impaired in the aged WT and Sesn2 KO versus young WT hearts by pressure overload. Intriguingly, pressure overload induced an interaction between Sestrin2 and GATOR2, a complex of unknown function that positively regulates mTORC1. Moreover, the binding affinity between Sestrin2 and GATOR2 is impaired in the aged WT hearts (p<0.05 vs. young WT). Furthermore, Adeno-associated virus 9 (AAV9)-Sestrin2 were delivered into the aged WT and Sesn2 KO hearts via a coronary delivery approach that rescued the protein levels of Sestrin2, attenuated mTORC1 activation and increased the tolerance of both aged WT and Sesn2 KO hearts to pressure overload. Conclusions: Cardiac Sestrin2 is a sensor for mTORC1 pathway in response to pressure overload. Sestrin2 deficiency in aging could be a reason for an increased sensitivity to hypertrophy in the elderly.

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