Targeting the mTOR Signaling Pathway Utilizing Nanoparticles: A Critical Overview

Proteins of the mammalian target of rapamycin (mTOR) signaling axis are overexpressed or mutated in cancers. However, clinical inhibition of mTOR signaling as a therapeutic strategy in oncology shows rather limited progress. Nanoparticle-based mTOR targeted therapy proposes an attractive therapeutic option for various types of cancers. Along with the progress in the biomedical applications of nanoparticles, we start to realize the challenges and opportunities that lie ahead. Here, we critically analyze the current literature on the modulation of mTOR activity by nanoparticles, demonstrate the complexity of cellular responses to functionalized nanoparticles, and underline challenges lying in the identification of the molecular mechanisms of mTOR signaling affected by nanoparticles. We propose the idea that subcytotoxic doses of nanoparticles could be relevant for the induction of subcellular structural changes with possible involvement of mTORC1 signaling. The evaluation of the mechanisms and therapeutic effects of nanoparticle-based mTOR modulation will provide fundamental knowledge which could help in developing safe and efficient nano-therapeutics.

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AMP-Activated Protein Kinase as a Key Trigger for the Disuse-Induced Skeletal Muscle Remodeling

International Journal of Molecular Sciences ◽

10.3390/ijms19113558 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3558 ◽

Cited By ~ 13

Author(s):

Natalia Vilchinskaya ◽

Igor Krivoi ◽

Boris Shenkman

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Histone Deacetylases ◽

Molecular Mechanisms ◽

Weight Bearing ◽

Mammalian Target Of Rapamycin ◽

Adenosine Monophosphate ◽

Chain Gene ◽

Mtorc1 Signaling ◽

The Impact

Molecular mechanisms that trigger disuse-induced postural muscle atrophy as well as myosin phenotype transformations are poorly studied. This review will summarize the impact of 5′ adenosine monophosphate -activated protein kinase (AMPK) activity on mammalian target of rapamycin complex 1 (mTORC1)-signaling, nuclear-cytoplasmic traffic of class IIa histone deacetylases (HDAC), and myosin heavy chain gene expression in mammalian postural muscles (mainly, soleus muscle) under disuse conditions, i.e., withdrawal of weight-bearing from ankle extensors. Based on the current literature and the authors’ own experimental data, the present review points out that AMPK plays a key role in the regulation of signaling pathways that determine metabolic, structural, and functional alternations in skeletal muscle fibers under disuse.

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SLC36A1-mTORC1 signaling drives acquired resistance to CDK4/6 inhibitors

Science Advances ◽

10.1126/sciadv.aax6352 ◽

2019 ◽

Vol 5 (9) ◽

pp. eaax6352 ◽

Cited By ~ 10

Author(s):

Akihiro Yoshida ◽

Yiwen Bu ◽

Shuo Qie ◽

John Wrangle ◽

E. Ramsay Camp ◽

...

Keyword(s):

Molecular Mechanisms ◽

Fragile X ◽

Acquired Resistance ◽

Mammalian Target Of Rapamycin ◽

Cyclin Dependent Kinase ◽

Solute Carrier Family ◽

Potential Therapeutic Target ◽

Mtorc1 Signaling ◽

Solute Carrier

The cyclin-dependent kinase 4/6 (CDK4/6) kinase is dysregulated in melanoma, highlighting it as a potential therapeutic target. CDK4/6 inhibitors are being evaluated in trials for melanoma and additional cancers. While beneficial, resistance to therapy is a concern, and the molecular mechanisms of such resistance remain undefined. We demonstrate that reactivation of mammalian target of rapamycin 1 (mTORC1) signaling through increased expression of the amino acid transporter, solute carrier family 36 member 1 (SLC36A1), drives resistance to CDK4/6 inhibitors. Increased expression of SLC36A1 reflects two distinct mechanisms: (i) Rb loss, which drives SLC36A1 via reduced suppression of E2f; (ii) fragile X mental retardation syndrome–associated protein 1 overexpression, which promotes SLC36A1 translation and subsequently mTORC1. Last, we demonstrate that a combination of a CDK4/6 inhibitor with an mTORC1 inhibitor has increased therapeutic efficacy in vivo, providing an important avenue for improved therapeutic intervention in aggressive melanoma.

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Muscle mTORC1 suppression by IL-6 during cancer cachexia: a role for AMPK

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00410.2012 ◽

2013 ◽

Vol 304 (10) ◽

pp. E1042-E1052 ◽

Cited By ~ 64

Author(s):

James P. White ◽

Melissa J. Puppa ◽

Song Gao ◽

Shuichi Sato ◽

Stephen L. Welle ◽

...

Keyword(s):

Skeletal Muscle ◽

Cancer Cachexia ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Mammalian Target Of Rapamycin ◽

Mtor Signaling ◽

Glucose Administration ◽

Mtorc1 Signaling ◽

Dose Dependent ◽

Mtor Activity

Although catabolic signaling has a well-established role in muscle wasting during cancer cachexia, the suppression of anabolic signaling also warrants further investigation. In cachectic tumor-bearing mice, circulating IL-6 levels are associated with suppressed muscle protein synthesis and mTORC1 signaling. We have found AMPK and IGF-I/insulin signaling, two well-known regulators of the mammalian target of rapamycin (mTOR), are altered with the progression of cachexia. How IL-6 can induce suppression of mTORC1 signaling remains to be established. The purpose of this study was to examine mTOR complex 1 (mTORC1) activation and regulation by IL-6 during cancer cachexia. IL-6 effects on mTOR activation were examined in Apc Min/+ mouse skeletal muscle and C2C12 myotubes. Systemic IL-6 overexpression in Apc Min/+ mice produced a dose-dependent suppression of mTOR signaling that corresponded to induction of STAT3 and AMPK phosphorylation. This result was also evident in IL-6-treated myotubes. Basal mTOR activation and mTOR responsiveness to glucose administration were suppressed in cachectic skeletal muscle. However, insulin induction of mTOR activity was maintained in IL-6-treated myotubes. Whereas IL-6 suppression of myotube mTOR activity was rescued by AMPK inhibition, inhibition of STAT3 signaling was not sufficient to rescue IL-6 suppression of mTOR activity. Last, treadmill exercise training was able to prevent IL-6-induced inhibition of mTOR signaling in Apc Min/+ mice independently of activated STAT. In conclusion, we report dose-dependent suppression of mTOR activity by IL-6 and suppressed mTOR responsiveness to glucose administration in Apc Min/+ mice. IL-6 suppression of mTOR activity was dependent on AMPK activation and independent of STAT signaling in myotubes.

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Glomerular Damage in Trichloroethylene-Sensitized Mice: Targeting Cathepsin L-Induced Hyperactive mTOR Signaling

Frontiers in Pharmacology ◽

10.3389/fphar.2021.639878 ◽

2021 ◽

Vol 12 ◽

Author(s):

Feng Wang ◽

Yuying Dai ◽

Meng Huang ◽

Chenchen Zhang ◽

Liping Huang ◽

...

Keyword(s):

Molecular Mechanisms ◽

Structural Integrity ◽

Health Hazard ◽

Cathepsin L ◽

Mtor Signaling ◽

Transmission Electron ◽

Immune Mediated ◽

Mtorc1 Signaling ◽

Podocyte Loss ◽

Glomerular Damage

Trichloroethylene (TCE) is a serious health hazard for workers with daily exposure, causing occupational medicamentosa-like dermatitis due to TCE (OMDT) and glomerular damage. Recent studies suggest that mTORC1 signaling is activated in various glomerular disorders; however, the role of mTORC1 signaling in TCE-induced glomerular damage remains to be explored. In the present study, 6 OMDT patients were enrolled and a TCE-sensitized mouse model was established to investigate molecular mechanisms underlying the glomerular damage associated with OMDT. Glomerular damage was assessed by levels of urine nephrin, H&E staining, and renal function test. Ultrastructural change of podocyte was investigated by transmission electron microscopy. The podocyte-related molecules including nephrin, α-actinin-4, and integrin β1 were visualized by immunofluorescence. The activation of mTORC1 signaling was confirmed by Western blot. Glomerular apoptosis was examined by the TUNEL test and Western blotting. Expression and location of cathepsin L (CTSL) were assessed by RT-PCR and immunofluorescence. Our results showed that TCE sensitization caused damage to glomerular structural integrity and also increased the activation of mTORC1 signaling, which was accompanied by podocyte loss, hypertrophy, and glomerular apoptosis. Importantly, we also found that over-expressed CTSL was mainly located in podocyte and CTSL inhibition could partially block the activation of mTORC1 signaling. Thus, our findings suggested a novel mechanism whereby hyperactive mTOR signaling contributes to TCE sensitization–induced and immune-mediated glomerular damage via CTSL activation.

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mTOR Signaling Pathway Regulates Sperm Quality in Older Men

Cells ◽

10.3390/cells8060629 ◽

2019 ◽

Vol 8 (6) ◽

pp. 629 ◽

Cited By ~ 3

Author(s):

Silva ◽

Cabral ◽

Correia ◽

Carvalho ◽

Sousa ◽

...

Keyword(s):

Signaling Pathway ◽

Molecular Mechanisms ◽

Sperm Quality ◽

Older Men ◽

Mtor Signaling ◽

Paternal Age ◽

Signaling Proteins ◽

Mtor Signaling Pathway ◽

Mtorc1 Signaling ◽

The Impact

: Understanding how age affects fertility becomes increasingly relevant as couples delay childbearing toward later stages of their lives. While the influence of maternal age on fertility is well established, the impact of paternal age is poorly characterized. Thus, this study aimed to understand the molecular mechanisms responsible for age-dependent decline in spermatozoa quality. To attain it, we evaluated the impact of male age on the activity of signaling proteins in two distinct spermatozoa populations: total spermatozoa fraction and highly motile/viable fraction. In older men, we observed an inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) in the highly viable spermatozoa population. On the contrary, when considering the entire spermatozoa population (including defective/immotile/apoptotic cells) our findings support an active mTORC1 signaling pathway in older men. Additionally, total spermatozoa fractions of older men presented increased levels of apoptotic/stress markers (e.g., cellular tumor antigen p53-TP53) and mitogen-activated protein kinases (MAPKs) activity. Moreover, we established that the levels of most signaling proteins analyzed were consistently and significantly altered in men more than 27 years of age. This study was the first to associate the mTOR signaling pathway with the age impact on spermatozoa quality. Additionally, we constructed a network of the sperm proteins associated with male aging, identifying TP53 as a central player in spermatozoa aging.

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Testosterone induces cardiomyocyte hypertrophy through mammalian target of rapamycin complex 1 pathway

Journal of Endocrinology ◽

10.1677/joe-09-0044 ◽

2009 ◽

Vol 202 (2) ◽

pp. 299-307 ◽

Cited By ~ 57

Author(s):

Francisco Altamirano ◽

César Oyarce ◽

Patricio Silva ◽

Marcela Toyos ◽

Carlos Wilson ◽

...

Keyword(s):

Molecular Mechanisms ◽

Mammalian Target Of Rapamycin ◽

Cardiac Cells ◽

Initiation Factor ◽

Target Of Rapamycin ◽

Cardiomyocyte Hypertrophy ◽

Akt Inhibitor ◽

Mtor Inhibition ◽

Akt Phosphorylation ◽

Mtorc1 Signaling

Elevated testosterone concentrations induce cardiac hypertrophy but the molecular mechanisms are poorly understood. Anabolic properties of testosterone involve an increase in protein synthesis. The mammalian target of rapamycin complex 1 (mTORC1) pathway is a major regulator of cell growth, but the relationship between testosterone action and mTORC1 in cardiac cells remains unknown. Here, we investigated whether the hypertrophic effects of testosterone are mediated by mTORC1 signaling in cultured cardiomyocytes. Testosterone increases the phosphorylation of mTOR and its downstream targets 40S ribosomal protein S6 kinase 1 (S6K1; also known as RPS6KB1) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). The S6K1 phosphorylation induced by testosterone was blocked by rapamycin and small interfering RNA to mTOR. Moreover, the hormone increased both extracellular-regulated kinase (ERK1/2) and protein kinase B (Akt) phosphorylation. ERK1/2 inhibitor PD98059 blocked the testosterone-induced S6K1 phosphorylation, whereas Akt inhibition (Akt-inhibitor-X) had no effect. Testosterone-induced ERK1/2 and S6K1 phosphorylation increases were blocked by either 1,2-bis(2-aminophenoxy)ethane-N,N,N,N-tetraacetic acid-acetoxymethylester or by inhibitors of inositol 1,4,5-trisphosphate (IP3) pathway: U-73122 and 2-aminoethyl diphenylborate. Finally, cardiomyocyte hypertrophy was evaluated by, the expression of β-myosin heavy chain, α-skeletal actin, cell size, and amino acid incorporation. Testosterone increased all four parameters and the increase being blocked by mTOR inhibition. Our findings suggest that testosterone activates the mTORC1/S6K1 axis through IP3/Ca2+ and MEK/ERK1/2 to induce cardiomyocyte hypertrophy.

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Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity

eLife ◽

10.7554/elife.11058 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 78

Author(s):

Bernadette Carroll ◽

Dorothea Maetzel ◽

Oliver DK Maddocks ◽

Gisela Otten ◽

Matthew Ratcliff ◽

...

Keyword(s):

Amino Acid ◽

Mammalian Target Of Rapamycin ◽

Embryonic Stem ◽

Cell Types ◽

Cellular Protein ◽

Small Gtpase ◽

Growth Factor Signaling ◽

Mtorc1 Signaling ◽

Signaling Axis ◽

Intracellular Amino Acids

The mammalian target of rapamycin complex 1 (mTORC1) is the key signaling hub that regulates cellular protein homeostasis, growth, and proliferation in health and disease. As a prerequisite for activation of mTORC1 by hormones and mitogens, there first has to be an available pool of intracellular amino acids. Arginine, an amino acid essential during mammalian embryogenesis and early development is one of the key activators of mTORC1. Herein, we demonstrate that arginine acts independently of its metabolism to allow maximal activation of mTORC1 by growth factors via a mechanism that does not involve regulation of mTORC1 localization to lysosomes. Instead, arginine specifically suppresses lysosomal localization of the TSC complex and interaction with its target small GTPase protein, Rheb. By interfering with TSC-Rheb complex, arginine relieves allosteric inhibition of Rheb by TSC. Arginine cooperates with growth factor signaling which further promotes dissociation of TSC2 from lysosomes and activation of mTORC1. Arginine is the main amino acid sensed by the mTORC1 pathway in several cell types including human embryonic stem cells (hESCs). Dependence on arginine is maintained once hESCs are differentiated to fibroblasts, neurons, and hepatocytes, highlighting the fundamental importance of arginine-sensing to mTORC1 signaling. Together, our data provide evidence that different growth promoting cues cooperate to a greater extent than previously recognized to achieve tight spatial and temporal regulation of mTORC1 signaling.

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RasGRP1 is a causal factor in the development of l-DOPA–induced dyskinesia in Parkinson’s disease

Science Advances ◽

10.1126/sciadv.aaz7001 ◽

2020 ◽

Vol 6 (18) ◽

pp. eaaz7001 ◽

Cited By ~ 7

Author(s):

Mehdi Eshraghi ◽

Uri Nimrod Ramírez-Jarquín ◽

Neelam Shahani ◽

Tommaso Nuzzo ◽

Arianna De Rosa ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Molecular Mechanisms ◽

Involuntary Movement ◽

Mammalian Target Of Rapamycin ◽

Mass Spectrometry Analysis ◽

Therapeutic Effects ◽

Nucleotide Exchange ◽

Spectrometry Analysis ◽

Macaque Model

The therapeutic effects of l-3,4-dihydroxyphenylalanine (l-DOPA) in patients with Parkinson’s disease (PD) severely diminishes with the onset of abnormal involuntary movement, l-DOPA–induced dyskinesia (LID). However, the molecular mechanisms that promote LID remain unclear. Here, we demonstrated that RasGRP1 [(guanine nucleotide exchange factor (GEF)] controls the development of LID. l-DOPA treatment rapidly up-regulated RasGRP1 in the striatum of mouse and macaque model of PD. The lack of RasGRP1 in mice (RasGRP1−/−) dramatically diminished LID without interfering with the therapeutic effects of l-DOPA. Besides acting as a GEF for Ras homolog enriched in the brain (Rheb), the activator of the mammalian target of rapamycin kinase (mTOR), RasGRP1 promotes l-DOPA–induced extracellular signal-regulated kinase (ERK) and the mTOR signaling in the striatum. High-resolution tandem mass spectrometry analysis revealed multiple RasGRP1 downstream targets linked to LID vulnerability. Collectively, the study demonstrated that RasGRP1 is a critical striatal regulator of LID.

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Coumarins and Gastrointestinal Cancer: A New Therapeutic Option?

Frontiers in Oncology ◽

10.3389/fonc.2021.752784 ◽

2021 ◽

Vol 11 ◽

Author(s):

Zarrin Banikazemi ◽

Seyed Mohammad Mirazimi ◽

Fatemeh Dashti ◽

Mohammad Reza Mazandaranian ◽

Maryam Akbari ◽

...

Keyword(s):

Antitumor Activity ◽

Molecular Mechanisms ◽

Therapeutic Option ◽

Alkylating Agents ◽

Angiogenesis Inhibitors ◽

Therapeutic Effects ◽

Telomerase Inhibitors ◽

Antimitotic Activity ◽

Life Threatening ◽

Hormone Antagonists

Cancers of the gastrointestinal (GI) tract are often life-threatening malignancies, which can be a severe burden to the health care system. Globally, the mortality rate from gastrointestinal tumors has been increasing due to the lack of adequate diagnostic, prognostic, and therapeutic measures to combat these tumors. Coumarin is a natural product with remarkable antitumor activity, and it is widely found in various natural plant sources. Researchers have explored coumarin and its related derivatives to investigate their antitumor activity, and the potential molecular mechanisms involved. These mechanisms include hormone antagonists, alkylating agents, inhibitors of angiogenesis, inhibitors of topoisomerase, inducers of apoptosis, agents with antimitotic activity, telomerase inhibitors, inhibitors of human carbonic anhydrase, as well as other potential mechanisms. Consequently, drug design and discovery scientists and medicinal chemists have collaborated to identify new coumarin-related agents in order to produce more effective antitumor drugs against GI cancers. Herein, we summarize the therapeutic effects of coumarin and its derivatives against GI cancer.

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Proteomics of autism and Alzheimer’s mouse models reveal common alterations in mTOR signaling pathway

Translational Psychiatry ◽

10.1038/s41398-021-01578-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Shira Mencer ◽

Maryam Kartawy ◽

Felix Lendenfeld ◽

Huda Soluh ◽

Manish Kumar Tripathi ◽

...

Keyword(s):

Signaling Pathway ◽

Mouse Models ◽

Neurological Disorders ◽

Large Scale ◽

Molecular Mechanisms ◽

Mammalian Target Of Rapamycin ◽

Autism Spectrum ◽

Novel Therapy ◽

Western Blots ◽

Mtorc1 Signaling

AbstractAutism spectrum disorder (ASD) and Alzheimer’s disease (AD) are two different neurological disorders that share common clinical features, such as language impairment, executive functions, and motor problems. A genetic convergence has been proposed as well. However, the molecular mechanisms of these pathologies are still not well understood. Protein S-nitrosylation (SNO), the nitric oxide (NO)-mediated posttranslational modification, targets key proteins implicated in synaptic and neuronal functions. Previously, we have shown that NO and SNO are involved in the InsG3680(+/+) ASD and P301S AD mouse models. Here, we performed large-scale computational biology analysis of the SNO-proteome followed by biochemical validation to decipher the shared mechanisms between the pathologies. This analysis pointed to the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway as one of the shared molecular mechanisms. Activation of mTOR in the cortex of both mouse models was confirmed by western blots that showed increased phosphorylation of RPS6, a major substrate of mTORC1. Other molecular alterations affected by SNO and shared between the two mouse models, such as synaptic-associated processes, PKA signaling, and cytoskeleton-related processes were also detected. This is the first study to decipher the SNO-related shared mechanisms between SHANK3 and MAPT mutations. Understanding the involvement of SNO in neurological disorders and its intersection between ASD and AD might help developing an effective novel therapy for both neuropathologies.

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