mTOR signaling pathway and mTOR inhibitors in cancer: progress and challenges

Cell & Bioscience, Journal Year: 2020, Volume and Issue: 10(1)

Published: March 10, 2020

Abstract Mammalian target of rapamycin (mTOR) regulates cell proliferation, autophagy, and apoptosis by participating in multiple signaling pathways the body. Studies have shown that mTOR pathway is also associated with cancer, arthritis, insulin resistance, osteoporosis, other diseases. The pathway, which often activated tumors, not only gene transcription protein synthesis to regulate proliferation immune differentiation but plays an important role tumor metabolism. Therefore, a hot anti-tumor therapy research. In recent years, variety newly discovered inhibitors entered clinical studies, drugs been proven high activity combination inhibitors. purpose this review introduce on apoptosis, growth, metabolism cells, research progress field.

Language: Английский

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Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Oct. 2, 2023

The mammalian target of rapamycin (mTOR) is a protein kinase that controls cellular metabolism, catabolism, immune responses, autophagy, survival, proliferation, and migration, to maintain homeostasis. mTOR signaling cascade consists two distinct multi-subunit complexes named complex 1/2 (mTORC1/2). catalyzes the phosphorylation several critical proteins like AKT, C, insulin growth factor receptor (IGF-1R), 4E binding 1 (4E-BP1), ribosomal S6 (S6K), transcription EB (TFEB), sterol-responsive element-binding (SREBPs), Lipin-1, Unc-51-like autophagy-activating kinases. plays central role in regulating translation, lipid synthesis, nucleotide biogenesis lysosomes, nutrient sensing, signaling. emerging pieces evidence have revealed constitutive activation pathway due mutations/amplification/deletion either its (mTORC1 mTORC2) or upstream targets responsible for aging, neurological diseases, human malignancies. Here, we provide detailed structure mTOR, complexes, comprehensive regulators, as well downstream effectors cascades biomolecules, autophagy. Additionally, summarize potential long noncoding RNAs (lncRNAs) an important modulator Importantly, highlighted disorders, cancers, cancer stem cells, drug resistance. discuss developments therapeutic targeting with improved anticancer efficacy benefit patients clinics.

Language: Английский

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Targeting autophagy to overcome drug resistance: further developments

Journal of Hematology & Oncology, Journal Year: 2020, Volume and Issue: 13(1)

Published: Nov. 25, 2020

Abstract Inhibiting cell survival and inducing death are the main approaches of tumor therapy. Autophagy plays an important role on intracellular metabolic homeostasis by eliminating dysfunctional or unnecessary proteins damaged aged cellular organelles to recycle their constituent metabolites that enable maintenance genetic stability even promotes drug resistance, which severely limits efficacy chemotherapeutic drugs. Currently, targeting autophagy has a seemingly contradictory effect suppress promote survival, makes resistance more confusing fuzzier. In review, we summarize regulation emerging ways, action some new therapeutic treat interfering with autophagy-related pathways. The full-scale understanding tumor-associated signaling pathways physiological functions will hopefully open possibilities for treatment improvement in clinical outcomes.

Language: Английский

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Targeting AKT/mTOR in Oral Cancer: Mechanisms and Advances in Clinical Trials

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(9), P. 3285 - 3285

Published: May 6, 2020

Oral cancer (OC) is a devastating disease that takes the lives of lots people globally every year. The current spectrum treatment modalities does not meet needs patients. heterogeneity demands personalized medicine or targeted therapies. Therefore, there an urgent need to identify potential targets for OC. Abundant evidence has suggested components protein kinase B (AKT)/ mammalian target rapamycin (mTOR) pathway are intrinsic factors carcinogenesis. AKT central proliferation and survival normal cells, its downstream protein, mTOR, also plays indispensable role in cellular processes. wide involvement AKT/mTOR been noted oral squamous cell carcinoma (OSCC). This axis significantly regulates various hallmarks cancer, like proliferation, survival, angiogenesis, invasion, metastasis, autophagy, epithelial-to-mesenchymal transition (EMT). Activated signaling associated with circadian signaling, chemoresistance radio-resistance OC cells. Several miRNAs, circRNAs lncRNAs modulate this pathway. association process tumorigenesis culminated identification specific inhibitors prevention In review, we discussed significance as therapeutic management article provided update on several emerged promising candidates interventions against OC/head neck (HNC) clinical studies.

Language: Английский

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LncRNA OIP5-AS1 inhibits ferroptosis in prostate cancer with long-term cadmium exposure through miR-128-3p/SLC7A11 signaling

Ecotoxicology and Environmental Safety, Journal Year: 2021, Volume and Issue: 220, P. 112376 - 112376

Published: May 26, 2021

Previous studies suggest that cadmium (Cd) is one of the causative factors prostate cancer (PCa), but effect chronic Cd exposure on PCa progression remains unclear. Besides, whether long noncoding RNAs (lncRNAs) are involved in regulation prolonged to needs be elucidated. In present study, we found serum concentration patients was positively correlated with Gleason score and tumor-node-metastasis (TNM) classification. To simulate PCa, subjected PC3 DU145 cells long-term, low-dose further examined tumor behavior. Functional identified promoted cell growth ferroptosis resistance vitro vivo. Furthermore, lncRNA OIP5-AS1 expression greatly elevated upon exposure. Dysregulation mediated Cd-induced ferroptosis. Mechanistically, demonstrated served as an endogenous sponge miR-128-3p regulate SLC7A11, a surrogate marker Moreover, decreased viability by enhancing Taken together, our data indicate promotes through miR-128-3p/SLC7A11 signaling.

Language: Английский

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Autophagy in health and disease: From molecular mechanisms to therapeutic target

MedComm, Journal Year: 2022, Volume and Issue: 3(3)

Published: July 10, 2022

Macroautophagy/autophagy is an evolutionally conserved catabolic process in which cytosolic contents, such as aggregated proteins, dysfunctional organelle, or invading pathogens, are sequestered by the double-membrane structure termed autophagosome and delivered to lysosome for degradation. Over past two decades, autophagy has been extensively studied, from molecular mechanisms, biological functions, implications various human diseases, development of autophagy-related therapeutics. This review will focus on latest research, covering mechanisms control biogenesis autophagosome-lysosome fusion, upstream regulatory pathways including AMPK MTORC1 pathways. We also provide a systematic discussion implication cancer, neurodegenerative disorders (Alzheimer disease, Parkinson Huntington's Amyotrophic lateral sclerosis), metabolic diseases (obesity diabetes), viral infection especially SARS-Cov-2 COVID-19, cardiovascular (cardiac ischemia/reperfusion cardiomyopathy), aging. Finally, we summarize pharmacological agents that have therapeutic potential clinical applications via targeting pathway. It believed decades hard work research eventually bring real tangible benefits improvement health diseases.

Language: Английский

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LncRNA NEAT1 promotes autophagy via regulating miR‐204/ATG3 and enhanced cell resistance to sorafenib in hepatocellular carcinoma

Journal of Cellular Physiology, Journal Year: 2019, Volume and Issue: 235(4), P. 3402 - 3413

Published: Sept. 23, 2019

Abstract Long noncoding RNAs (lncRNAs) has been acknowledged in tumorigenesis gradually because of the great importance different cancers. LncRNA nuclear enriched abundant transcript 1 (NEAT1) is a novel lncRNA and reported to promote multiple cancer progression. However, biological roles NEAT1 hepatocellular carcinoma (HCC) not cleared nowadays. In present research, level was found be upregulated HCC by The Cancer Genome Atlas. addition, expression negatively correlated with survival rate HCC. Further investigation revealed that upregulation inhibited sorafenib efficacy promoted autophagy. We could sponge for microRNA‐204 (miR‐204) inhibits its upregulate ATG3 expression. addition above, we demonstrated miR‐204 mimics also attenuated tumor And rescue assays promotes autophagy through modulating miR‐204/ATG3 pathway. Collectively, this study first NEAT1/miR‐204/ATG3 signaling regulates

Language: Английский

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Multi-faceted epigenetic dysregulation of gene expression promotes esophageal squamous cell carcinoma

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: July 22, 2020

Abstract Epigenetic landscapes can shape physiologic and disease phenotypes. We used integrative, high resolution multi-omics methods to delineate the methylome landscape characterize oncogenic drivers of esophageal squamous cell carcinoma (ESCC). found 98% CpGs are hypomethylated across ESCC genome. Hypo-methylated regions enriched in areas with heterochromatin binding markers (H3K9me3, H3K27me3), while hyper-methylated polycomb repressive complex (EZH2/SUZ12) recognizing regions. Altered methylation promoters, enhancers, gene bodies, as well occupancy CTCF sites associated cancer-specific dysregulation. Epigenetic-mediated activation non-canonical WNT/β-catenin/MMP signaling a YY1/lncRNA ESCCAL-1/ribosomal protein network uncovered validated potential novel driver alterations. This study advances our understanding how epigenetic cancer pathogenesis provides resource for biomarker target discovery.

Language: Английский

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The role of non‐coding RNAs in drug resistance of oral squamous cell carcinoma and therapeutic potential

Cancer Communications, Journal Year: 2021, Volume and Issue: 41(10), P. 981 - 1006

Published: July 20, 2021

Oral squamous cell carcinoma (OSCC), the eighth most prevalent cancer in world, arises from interaction of multiple factors including tobacco, alcohol consumption, and betel quid. Chemotherapeutic agents such as cisplatin, 5-fluorouracil, paclitaxel have now become first-line options for OSCC patients. Nevertheless, patients eventually acquire drug resistance, leading to poor prognosis. With discovery identification non-coding RNAs (ncRNAs), functions dysregulated ncRNAs development resistance are gradually being widely recognized. The mechanisms intricate involve efflux, epithelial-mesenchymal transition, DNA damage repair, autophagy. At present, strategies explore reversal need be urgently developed. Nano-delivery self-cellular delivery platforms considered effective overcome due their tumor targeting, controlled release, consistent pharmacokinetic profiles. In particular, combined application new technologies (including CRISPR systems) opened up horizons treatment OSCC. Hence, this review explored emerging regulatory OSCC, elucidated ncRNA-meditated discussed potential value using nanoparticles self-cells carriers

Language: Английский

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SPAG5‐AS1 inhibited autophagy and aggravated apoptosis of podocytes via SPAG5/AKT/mTOR pathway

Cell Proliferation, Journal Year: 2020, Volume and Issue: 53(2)

Published: Jan. 19, 2020

Abstract Objectives Podocyte injury is a prediction marker of diabetic nephropathy (DN), and AKT/mTOR pathway–mediated inhibition autophagy widely reported to contribute podocyte damage. Recent study stated that sperm‐associated antigen 5 (SPAG5) activated signalling in bladder urothelial carcinoma, indicating SPAG5 might regulate play role Materials methods Apoptosis human podocytes (HPCs) were detected by flow cytometry immunofluorescence (IF). Gene level was assessed Western blot RT‐qPCR. Molecular interactions determined pulldown, RNA immunoprecipitation (RIP), co‐immunoprecipitation (co‐IP), chromatin (ChIP) luciferase reporter assays. Results mRNA protein levels upregulated under high glucose treatment HPCs. Silencing reversed the increase apoptosis decrease glucose–treated Later, we found long non‐coding (lncRNA) antisense RNA1 (SPAG5‐AS1) as neighbour gene SPAG5. Mechanistically, YY1 transcriptionally SPAG5‐AS1 podocytes. acted competitive endogenous (ceRNA) miR‐769‐5p/YY1 axis induce interacted with ubiquitin‐specific peptidase 14 (USP14) leads de‐ubiquitination stabilization protein. Conclusions This revealed inhibited aggravated via SPAG5/AKT/mTOR pathway, SPAG5‐AS1/SPAG5 potential target for alleviation offering new thoughts treatments DN.

Language: Английский

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