Targeting PI3K/Akt signal transduction for cancer therapy

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: Dec. 16, 2021

Abstract The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays a crucial role in various cellular processes and is aberrantly activated cancers, contributing to the occurrence progression of tumors. Examining upstream downstream nodes this could allow full elucidation its function. Based on accumulating evidence, strategies targeting major components might provide new insights for cancer drug discovery. Researchers have explored use some inhibitors block survival pathways. However, because oncogenic PI3K activation occurs through mechanisms, clinical efficacies these are limited. Moreover, accompanied by development therapeutic resistance. Therefore, involving other treatments combination solve dilemma. In review, we discuss roles PI3K/Akt phenotypes, review current statuses different inhibitors, introduce therapies consisting signaling conventional therapies. information presented herein suggests that cascading pathway, either alone or with therapies, most effective treatment strategy cancer.

Language: Английский

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RETRACTED ARTICLE: Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours

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

Published: April 1, 2020

Abstract The PI3 K/AKT/mTOR signalling pathway plays an important role in the regulation of signal transduction and biological processes such as cell proliferation, apoptosis, metabolism angiogenesis. Compared with those other pathways, components PI3K/AKT/mTOR are complicated. regulatory mechanisms functions many human diseases, including ischaemic brain injury, neurodegenerative tumours. inhibitors include single-component dual inhibitors. Numerous PI3K have exhibited good results preclinical studies, some been clinically tested haematologic malignancies solid In this review, we briefly summarize research on discuss structural composition, activation, communication processes, pathogenesis diseases

Language: Английский

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PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway?

Frontiers in Oncology, Journal Year: 2022, Volume and Issue: 12

Published: March 24, 2022

Cancer is a severe public health issue that leading cause of mortality globally. It also an impediment to improving life expectancy worldwide. Furthermore, the global burden cancer incidence and death continuously growing. Current therapeutic options are insufficient for patients, tumor complexity heterogeneity necessitate customized medicine or targeted therapy. critical identify potential targets. Aberrant activation PI3K/AKT/mTOR pathway has significant role in carcinogenesis. This review summarized oncogenic PI3K/Akt/mTOR alterations various hallmarks associated with pathway, such as cell proliferation, autophagy, apoptosis, angiogenesis, epithelial-to-mesenchymal transition (EMT), chemoresistance. Importantly, this provided recent advances inhibitor research. Overall, in-depth understanding association between tumorigenesis development therapies targeting will help make clinical decisions.

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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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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Metabolism of Amino Acids in Cancer

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 8

Published: Jan. 12, 2021

Metabolic reprogramming has been widely recognized as a hallmark of malignancy. The uptake and metabolism amino acids are aberrantly upregulated in many cancers that display addiction to particular acids. Amino facilitate the survival proliferation cancer cells under genotoxic, oxidative, nutritional stress. Thus, targeting acid is becoming potential therapeutic strategy for patients. In this review, we will systematically summarize recent progress malignancy discuss their interconnection with mammalian target rapamycin complex 1 (mTORC1) signaling, epigenetic modification, tumor growth immunity, ferroptosis. Finally, highlight applications.

Language: Английский

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The Pathogenic Role of PI3K/AKT Pathway in Cancer Onset and Drug Resistance: An Updated Review

Cancers, Journal Year: 2021, Volume and Issue: 13(16), P. 3949 - 3949

Published: Aug. 5, 2021

The PI3K/AKT pathway is one of the most frequently over-activated intracellular pathways in several human cancers. This pathway, acting on different downstream target proteins, contributes to carcinogenesis, proliferation, invasion, and metastasis tumour cells. A multi-level impairment, involving mutation genetic alteration, aberrant regulation miRNAs sequences, abnormal phosphorylation cascade factors, has been found multiple cancer types. deregulation this counteracts common therapeutic strategies multidrug resistance. In review, we underline involvement patho-physiological cell survival mechanisms, emphasizing its key role development drug We also provide an overview potential inhibition currently available.

Language: Английский

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MiR-199a-modified exosomes from adipose tissue-derived mesenchymal stem cells improve hepatocellular carcinoma chemosensitivity through mTOR pathway

Journal of Experimental & Clinical Cancer Research, Journal Year: 2020, Volume and Issue: 39(1)

Published: Jan. 2, 2020

MiR-199a-3p (miR-199a) can enhance the chemosensitivity of hepatocellular carcinoma (HCC). Because easy degradation miRNA by direct infusion, effective vehicle-mediated delivery miR-199a may represent a new strategy for improving HCC chemotherapy. Considering mesenchymal stem cell (MSC)-derived exosomes as promising natural nanovectors drug and molecule delivery, we aimed to determine whether from adipose tissue-derived MSCs (AMSCs) could be used deliver improve chemosensitivity.MiR-199a-modified AMSCs (AMSC-199a) were constructed lentivirus infection puromycin selection. MiR-199-modified (AMSC-Exo-199a) isolated supernatant AMSC-199a assessed transmission electron microscopy, nanoparticle tracking analysis, flow cytometry analysis. The expression levels in samples, AMSCs, exosomes, cells quantified real-time PCR. effects AMSC-Exo-199a on determined proliferation apoptosis assays i.v. injection into orthotopic mouse models with doxorubicin treatment. MTOR, p-4EBP1 p-70S6K tissues Western blot.AMSC-Exo-199a had classic characteristics effectively mediate cells. Additionally, significantly sensitized targeting mTOR subsequently inhibiting pathway. Moreover, i.v.-injected distribute tumor tissue markedly increased effect Dox against vivo.AMSC-Exo-199a an vehicle they chemotherapeutic agents administration provide chemosensitivity.

Language: Английский

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The Role of mTOR Signaling as a Therapeutic Target in Cancer

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(4), P. 1743 - 1743

Published: Feb. 9, 2021

The aim of this review was to summarize current available information about the role phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target rapamycin (mTOR) signaling in cancer as a potential for new therapy options. mTOR and PI3K/AKT/mTORC1 (mTOR complex 1) are critical regulation many fundamental cell processes including protein synthesis, growth, metabolism, survival, catabolism, autophagy, deregulated is implicated cancer, metabolic dysregulation, aging process. In review, we structure function pathway discuss mechanisms its deregulation human cancers genetic alterations PI3K/AKT/mTOR components. We also present recent data regarding inhibitors clinical studies treatment well attendant problems resistance adverse effects.

Language: Английский

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Fin56-induced ferroptosis is supported by autophagy-mediated GPX4 degradation and functions synergistically with mTOR inhibition to kill bladder cancer cells

Cell Death and Disease, Journal Year: 2021, Volume and Issue: 12(11)

Published: Oct. 29, 2021

Abstract Ferroptosis is a form of regulated cell death that emerges to be relevant for therapy-resistant and dedifferentiating cancers. Although several lines evidence suggest ferroptosis type autophagy-dependent death, the underlying molecular mechanisms remain unclear. Fin56, 3 inducer, triggers by promoting glutathione peroxidase 4 (GPX4) protein degradation via not fully understood pathway. Here, we determined Fin56 induces autophagy in bladder cancer cells Fin56-triggered mechanistically depends on autophagic machinery. Furthermore, found inhibition at different stages attenuates Fin56-induced oxidative stress GPX4 degradation. Moreover, investigated effects combination with Torin 2, potent mTOR inhibitor used activate autophagy, viability. We synergizes 2 cytotoxicity against cells. Collectively, our findings only support concept but imply combined application inducers inhibitors promising approach improve therapeutic options treatment cancer.

Language: Английский

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