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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Osteoarthritis: pathogenic signaling pathways and therapeutic targets

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

Published: Feb. 3, 2023

Abstract Osteoarthritis (OA) is a chronic degenerative joint disorder that leads to disability and affects more than 500 million population worldwide. OA was believed be caused by the wearing tearing of articular cartilage, but it now commonly referred as whole-joint initiated with biochemical cellular alterations in synovial tissues, which histological structural changes ends up whole tissue dysfunction. Currently, there no cure for OA, partly due lack comprehensive understanding pathological mechanism initiation progression disease. Therefore, better signaling pathways key molecules involved pathogenesis crucial therapeutic target design drug development. In this review, we first summarize epidemiology including its prevalence, incidence burdens, risk factors. We then focus on roles regulation pathways, such Wnt/β-catenin, NF-κB, focal adhesion, HIFs, TGFβ/ΒΜP FGF regulators AMPK, mTOR, RUNX2 onset development OA. addition, factors associated MMPs, ADAMTS/ADAMs, PRG4, are discussed detail. Finally, provide updates current clinical therapies trials biological treatments drugs Research advances basic knowledge cartilage biology will have significant impact translational value developing strategies.

Language: Английский

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Metabolic coordination of T cell quiescence and activation

Nature reviews. Immunology, Journal Year: 2019, Volume and Issue: 20(1), P. 55 - 70

Published: Aug. 12, 2019

Language: Английский

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The role of ubiquitination in tumorigenesis and targeted drug discovery

Signal Transduction and Targeted Therapy, Journal Year: 2020, Volume and Issue: 5(1)

Published: Feb. 29, 2020

Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" "quality" various proteins, serving to ensure cell homeostasis guarantee life activities. The regulation ubiquitination is multifaceted works not only at transcriptional levels (phosphorylation, acetylation, methylation, etc.) but also level (activators or repressors). When regulatory mechanisms are aberrant, altered biological processes may induce serious human diseases, especially types cancer. In tumorigenesis, involve tumor metabolism, immunological microenvironment (TME), cancer stem (CSC) stemness so on. With regard some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc P53 significantly regulates activity mTORC1, AMPK PTEN-AKT signaling pathways. addition, TLR, RLR STING-dependent pathways modulates TME. Moreover, core regulator triplets (Nanog, Oct4 Sox2) members Wnt Hippo-YAP participates maintenance CSC stemness. Based on components, including proteasome, E3 ligases, E1, E2 deubiquitinases (DUBs), many molecular targeted drugs have been developed combat Among them, small molecule inhibitors targeting bortezomib, carfilzomib, oprozomib ixazomib, achieved tangible success. MLN7243 MLN4924 (targeting E1 enzyme), Leucettamol A CC0651 nutlin MI-219 compounds G5 F6 DUB activity) shown potential preclinical treatment. this review, we summarize latest progress understanding substrates for their special functions metabolism regulation, TME modulation maintenance. therapeutic targets reviewed, effects drugs.

Language: Английский

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mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy

International Journal of Molecular Sciences, Journal Year: 2019, Volume and Issue: 20(3), P. 755 - 755

Published: Feb. 11, 2019

The mammalian or mechanistic target of rapamycin (mTOR) pathway plays a crucial role in regulation cell survival, metabolism, growth and protein synthesis response to upstream signals both normal physiological pathological conditions, especially cancer. Aberrant mTOR signaling resulting from genetic alterations different levels the signal cascade is commonly observed various types cancers. Upon hyperactivation, promotes proliferation metabolism that contribute tumor initiation progression. In addition, also negatively regulates autophagy via ways. We discuss its key downstream factors, specific changes inhibitors applied as therapeutic strategies eight solid tumors. Although monotherapy combination therapy with have been extensively preclinical clinical trials cancer types, innovative therapies better efficacy less drug resistance are still great need, new biomarkers deep sequencing technologies will facilitate these targeting drugs benefit patients personalized therapy.

Language: Английский

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mTOR: Role in cancer, metastasis and drug resistance

Seminars in Cancer Biology, Journal Year: 2019, Volume and Issue: 59, P. 92 - 111

Published: Aug. 10, 2019

Language: Английский

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Attacking the PI3K/Akt/mTOR signaling pathway for targeted therapeutic treatment in human cancer

Seminars in Cancer Biology, Journal Year: 2021, Volume and Issue: 85, P. 69 - 94

Published: June 25, 2021

Language: Английский

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Sex differences in cancer mechanisms

Biology of Sex Differences, Journal Year: 2020, Volume and Issue: 11(1)

Published: April 15, 2020

We now know that cancer is many different diseases, with great variation even within a single histological subtype. With the current emphasis on developing personalized approaches to treatment, it astonishing we have not yet systematically incorporated biology of sex differences into our paradigms for laboratory and clinical research. While some in arise through actions circulating hormones, other are independent estrogen, testosterone, or progesterone levels. Instead, these result sexual differentiation, process involves genetic epigenetic mechanisms, addition acute hormone actions. Sexual differentiation begins fertilization continues beyond menopause. It affects virtually every body system, resulting marked such areas as growth, lifespan, metabolism, immunity, all which can impact progression, treatment response, survival. These organismal level correlates at cellular level, thus, males females fundamentally differ their protections vulnerabilities cancer, from transformation stages spread, response treatment. Our goal this review cover robust exist core pathways make case inclusion biological variable finish discussion lab- clinic-based experimental design should be used when testing whether matters appropriate statistical models apply data analysis rigorous evaluations potential effects. facilitate evaluation order improve outcomes patients.

Language: Английский

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Meta-hallmarks of aging and cancer

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(1), P. 12 - 35

Published: Jan. 1, 2023

Language: Английский

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Lactate in the tumour microenvironment: From immune modulation to therapy

EBioMedicine, Journal Year: 2021, Volume and Issue: 73, P. 103627 - 103627

Published: Oct. 15, 2021

Disordered metabolic states, which are characterised by hypoxia and elevated levels of metabolites, particularly lactate, contribute to the immunosuppression in tumour microenvironment (TME). Excessive lactate secreted metabolism-reprogrammed cancer cells regulates immune responses via causing extracellular acidification, acting as an energy source shuttling between different cell populations, inhibiting mechanistic (previously 'mammalian') target rapamycin (mTOR) pathway cells. This review focuses on recent advances regulation well therapeutic strategies targeting anabolism transport TME, such those involving glycolytic enzymes monocarboxylate transporter inhibitors. Considering multifaceted roles metabolism, a comprehensive understanding how lactate-targeting therapies regulate TME will provide insights into complex relationships metabolism antitumour immunity.

Language: Английский

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