PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer

Molecular Cancer, Год журнала: 2023, Номер 22(1)

Опубликована: Авг. 18, 2023

Abstract The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, growth, and cycle progression. Growth factor signalling to transcription factors the PAM axis regulated by multiple cross-interactions with several other pathways, dysregulation of can predispose cancer development. most frequently activated human often implicated resistance anticancer therapies. Dysfunction components this such as hyperactivity PI3K, loss function PTEN, gain-of-function AKT, are notorious drivers treatment disease progression cancer. In review we highlight major dysregulations cancer, discuss results AKT mTOR inhibitors monotherapy co-administation antineoplastic agents clinical trials strategy for overcoming resistance. Finally, mechanisms targeted therapies, including immunology immunotherapies also discussed.

Язык: Английский

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The Keap1‐Nrf2 System: A Mediator between Oxidative Stress and Aging

Oxidative Medicine and Cellular Longevity, Год журнала: 2021, Номер 2021(1)

Опубликована: Янв. 1, 2021

Oxidative stress, a term that describes the imbalance between oxidants and antioxidants, leads to disruption of redox signals causes molecular damage. Increased oxidative stress from diverse sources has been implicated in most senescence‐related diseases aging itself. The Kelch‐like ECH‐associated protein 1‐ (Keap1‐) nuclear factor‐erythroid 2‐related factor 2 (Nrf2) system can be used monitor stress; Keap1‐Nrf2 is closely associated with controls transcription multiple antioxidant enzymes. Simultaneously, signaling also modulated by more complex regulatory network, including phosphoinositide 3‐kinase (PI3K)/protein kinase B (Akt), C, mitogen‐activated kinase. This review presents information on aging‐related mechanisms involving Keap1‐Nrf2. Furthermore, we highlight several major involved Nrf2 unbinding Keap1, cysteine modification Keap1 phosphorylation Nrf2, PI3K/Akt/glycogen synthase 3 β , sequestosome 1, Bach1 c ‐ Myc . Additionally, discuss direct interaction mammalian target rapamycin pathway. In summary, focus recent progress research aging, providing an empirical basis for development antiaging drugs.

Язык: Английский

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

Cancers, Год журнала: 2021, Номер 13(16), С. 3949 - 3949

Опубликована: Авг. 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.

Язык: Английский

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The Influence of Cell Cycle Regulation on Chemotherapy

International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(13), С. 6923 - 6923

Опубликована: Июнь 28, 2021

Cell cycle regulation is orchestrated by a complex network of interactions between proteins, enzymes, cytokines, and cell signaling pathways, vital for proliferation, growth, repair. The occurrence, development, metastasis tumors are closely related to the cycle. can be synergistic with chemotherapy in two aspects: inhibition or promotion. sensitivity tumor cells chemotherapeutic drugs improved cooperation strategies. This review presented mechanism commonly used effect on tumorigenesis interaction cancer treatment was briefly introduced. current collaborative strategies discussed detail. Finally, we outline challenges perspectives about improvement combination therapy.

Язык: Английский

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Emerging role of PI3K/AKT in tumor-related epigenetic regulation

Seminars in Cancer Biology, Год журнала: 2019, Номер 59, С. 112 - 124

Опубликована: Апрель 2, 2019

Язык: Английский

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Wnt and PI3K/Akt/mTOR Survival Pathways as Therapeutic Targets in Glioblastoma

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(3), С. 1353 - 1353

Опубликована: Янв. 25, 2022

Glioblastoma (GBM) is a devastating type of brain tumor, and current therapeutic treatments, including surgery, chemotherapy, radiation, are palliative at best. The design effective targeted chemotherapeutic strategies for the treatment GBM require thorough analysis specific signaling pathways to identify those serving as drivers progression invasion. Wnt/β-catenin PI3K/Akt/mTOR (PAM) key regulators important biological functions that include cell proliferation, epithelial–mesenchymal transition (EMT), metabolism, angiogenesis. Targeting regulatory components PAM has potential disrupt critical tumor achieve advancements in alternative enhance survival rate patients. In this review, we emphasize importance invasion into tissue explore their targets.

Язык: Английский

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Insulin action at a molecular level – 100 years of progress

Molecular Metabolism, Год журнала: 2021, Номер 52, С. 101304 - 101304

Опубликована: Июль 15, 2021

The discovery of insulin 100 years ago and its application to the treatment human disease in since have marked a major turning point history medicine. availability purified allowed for establishment physiological role regulation blood glucose ketones, determination amino acid sequence, solving structure. Over last 50 years, function has been applied into receptor signaling cascade reveal impaired signaling—or resistance—in progression type 2 diabetes. It also become clear that can impact not only classical insulin-sensitive tissues, but all tissues body, many these regulates unexpected functions. Despite remarkable advances, much remains be learned about both how use this molecular knowledge advance diabetes other insulin-resistant states.

Язык: Английский

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Targeting autophagy in disease: established and new strategies

Autophagy, Год журнала: 2021, Номер 18(3), С. 473 - 495

Опубликована: Июль 9, 2021

Macroautophagy/autophagy is an evolutionarily conserved pathway responsible for clearing cytosolic aggregated proteins, damaged organelles or invading microorganisms. Dysfunctional autophagy leads to pathological accumulation of the cargo, which has been linked a range human diseases, including neurodegenerative infectious and autoimmune diseases various forms cancer. Cumulative work in animal models, application genetic tools pharmacologically active compounds, suggested potential therapeutic value modulation disease, as diverse Huntington, Salmonella infection, pancreatic Autophagy activation versus inhibition strategies are being explored, while role pathophysiology studied parallel. However, progress preclinical clinical development modulators greatly hampered by paucity selective pharmacological agents biomarkers dissect their precise impact on cellular responses. Here, we summarize established new autophagy-related drug discovery indicate path toward establishing more efficient autophagy-selective agents. With this knowledge at hand, modern concepts exploitation might become plausible.Abbreviations: ALS: amyotrophic lateral sclerosis; AMPK: AMP-activated protein kinase; ATG: gene; AUTAC: autophagy-targeting chimera; CNS: central nervous system; CQ: chloroquine; GABARAP: gamma-aminobutyric acid type A receptor-associated protein; HCQ: hydroxychloroquine; LYTAC: lysosome targeting MAP1LC3/LC3: microtubule associated 1 light chain 3; MTOR: mechanistic target rapamycin NDD: disease; PDAC: ductal adenocarcinoma; PE: phosphatidylethanolamine; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit PtdIns3K: class III 3-kinase; PtdIns3P: 3-phosphate; PROTAC: proteolysis-targeting SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like activating kinase 1.

Язык: Английский

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The PI3K/Akt signaling axis in Alzheimer’s disease: a valuable target to stimulate or suppress?

Cell Stress and Chaperones, Год журнала: 2021, Номер 26(6), С. 871 - 887

Опубликована: Авг. 13, 2021

Among the long list of age-related complications, Alzheimer's disease (AD) has most dreadful impact on quality life due to its devastating effects memory and cognitive abilities. Although a plausible correlation between phosphatidylinositol 3-kinase (PI3K) signaling different processes involved in neurodegeneration been evidenced, few articles reviewed task. The current review aims unravel mechanisms by which PI3K pathway plays pro-survival roles normal conditions, also discuss original data obtained from international research laboratories this topic. Responses questions how alterations PI3K/Akt affect Tau phosphorylation amyloid cascade are given. In addition, we provide general overview association oxidative stress, neuroinflammation, insulin signaling, altered autophagy with aberrant activation axis AD brain. last section provides special focus therapeutic possibility PI3K/Akt/mTOR modulators, either categorized as chemicals or herbals, AD. conclusion, determining correct timing for administration drugs seems be one important factors success these agents. Also, role progression repression widely depends context cells; generally speaking, while neurons neural stem cells is favorable, microglia may harmful.

Язык: Английский

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Apoptosis in Alzheimer’s disease: insight into the signaling pathways and therapeutic avenues

APOPTOSIS, Год журнала: 2023, Номер 28(7-8), С. 943 - 957

Опубликована: Апрель 26, 2023

Язык: Английский

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