Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons

Journal of Experimental & Clinical Cancer Research, Journal Year: 2021, Volume and Issue: 40(1)

Published: Jan. 11, 2021

Abstract Solid tumors often grow in a micro-environment characterized by < 2% O 2 tension. This condition, together with the aberrant activation of specific oncogenic patwhays, increases amount and activity hypoxia-inducible factor-1α (HIF-1α), transcription factor that controls up to 200 genes involved neoangiogenesis, metabolic rewiring, invasion drug resistance. Hypoxia also induces endoplasmic reticulum (ER) stress, condition triggers cell death, if cells are irreversibly damaged, or survival, stress is mild. chronic ER both induce chemoresistance. In this review we discuss multiple interconnected circuitries link hypoxic environment, We suggest hypoxia train select more adapted survive unfavorable conditions, activating pleiotropic mechanisms including apoptosis inhibition, anti-oxidant defences, drugs efflux. adaptative process unequivocally expands clones acquire resistance chemotherapy. believe pharmacological inhibitors HIF-1α modulators although low specificty anti-cancer efficacy when used as single agents, may be repurposed chemosensitizers against chemorefractory next future.

Language: Английский

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Tumor microenvironment signaling and therapeutics in cancer progression

Cancer Communications, Journal Year: 2023, Volume and Issue: 43(5), P. 525 - 561

Published: April 2, 2023

Abstract Tumor development and metastasis are facilitated by the complex interactions between cancer cells their microenvironment, which comprises stromal extracellular matrix (ECM) components, among other factors. Stromal can adopt new phenotypes to promote tumor cell invasion. A deep understanding of signaling pathways involved in cell‐to‐cell cell‐to‐ECM is needed design effective intervention strategies that might interrupt these interactions. In this review, we describe microenvironment (TME) components associated therapeutics. We discuss clinical advances prevalent newly discovered TME, immune checkpoints immunosuppressive chemokines, currently used inhibitors targeting pathways. These include both intrinsic non‐autonomous TME: protein kinase C (PKC) signaling, Notch, transforming growth factor (TGF‐β) Endoplasmic Reticulum (ER) stress response, lactate Metabolic reprogramming, cyclic GMP–AMP synthase (cGAS)–stimulator interferon genes (STING) Siglec also recent Programmed Cell Death Protein 1 (PD‐1), Cytotoxic T‐Lymphocyte Associated 4 (CTLA4), T‐cell immunoglobulin mucin‐3 (TIM‐3) Lymphocyte Activating Gene 3 (LAG3) checkpoint along with C‐C chemokine receptor (CCR4)‐ class chemokines 22 (CCL22)/ 17 (CCL17), type 2 (CCR2)‐ (C‐C motif) ligand (CCL2), 5 (CCR5)‐ (CCL3) axis TME. addition, review provides a holistic TME as three‐dimensional microfluidic models believed recapitulate original characteristics patient hence may be platform study mechanisms screen for various anti‐cancer therapies. further systemic influences gut microbiota reprogramming treatment response. Overall, comprehensive analysis diverse most critical highlighting newest preclinical studies underlying biology. highlight importance technologies microfluidics lab‐on‐chip research present an overview extrinsic factors, such inhabitant human microbiome, have potential modulate biology drug responses.

Language: Английский

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Nonsense-mediated RNA decay: an emerging modulator of malignancy

Nature reviews. Cancer, Journal Year: 2022, Volume and Issue: 22(8), P. 437 - 451

Published: May 27, 2022

Language: Английский

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The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2

Cell Reports, Journal Year: 2023, Volume and Issue: 42(7), P. 112724 - 112724

Published: July 1, 2023

The redox regulator NRF2 becomes activated upon oxidative and electrophilic stress orchestrates a response program associated with regulation, metabolism, tumor therapy resistance, immune suppression. Here, we describe an unrecognized link between the integrated (ISR) mediated by ISR effector ATF4. is commonly after starvation or ER plays central role in tissue homeostasis cancer plasticity. ATF4 increases transcription induces glutathione-degrading enzyme CHAC1, which now show to be critically important for maintaining activation. In-depth analyses reveal that supports ATF4-induced cells increasing cystine uptake via glutamate-cystine antiporter xCT. In addition, upregulates genes mediating thioredoxin usage regeneration, thus balancing glutathione decrease. conclusion, demonstrate serves as second layer of ISR, observation highly relevant understanding cellular resilience health disease.

Language: Английский

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Endoplasmic reticulum stress and therapeutic strategies in metabolic, neurodegenerative diseases and cancer

Molecular Medicine, Journal Year: 2024, Volume and Issue: 30(1)

Published: March 20, 2024

Abstract The accumulation of unfolded or misfolded proteins within the endoplasmic reticulum (ER), due to genetic determinants and extrinsic environmental factors, leads stress (ER stress). As ER ensues, protein response (UPR), comprising three signaling pathways—inositol-requiring enzyme 1, kinase R-like kinase, activating transcription factor 6 promptly activates enhance ER’s protein-folding capacity restore homeostasis. However, prolonged levels propels UPR towards cellular demise subsequent inflammatory cascade, contributing development human diseases, including cancer, neurodegenerative disorders, diabetes. Notably, increased expression all pathways has been observed in these pathologies, reduction molecule correlates with decreased proliferation disease-associated target cells. Consequently, therapeutic strategies targeting stress-related interventions have attracted significant research interest. In this review, we elucidate critical role metabolic, offering novel approaches for conditions.

Language: Английский

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Connections between endoplasmic reticulum stress-associated unfolded protein response, mitochondria, and autophagy in arsenic-induced carcinogenesis

Seminars in Cancer Biology, Journal Year: 2021, Volume and Issue: 76, P. 258 - 266

Published: April 6, 2021

Arsenic exposure in contaminated drinking water is a global health issue, as more than 200 million people are affected globally. has been known to cause skin, liver, lung, bladder and prostate cancers. Accordingly, it categorized group I human carcinogen by the International Agency for Research on Cancer (IARC). Various natural anthropogenic activities lead release of arsenic environment, contaminating air, food sources. Traditionally, genetic mutations have center cancer research. However, emerging studies now focused importance epigenetics, metabolism endoplasmic reticulum (ER) stress cancer. highly capable inducing cells via generation free radicals causing oxidative stress, epigenetic alterations, mitochondrial dysfunction, activation intracellular signaling pathways, impairment autophagy DNA repair systems. The able utilize unfolded protein response (UPR) overcome these internal stresses various stages arsenic-induced carcinogenesis, from growth immune responses. UPR an evolutionarily conserved that both survival apoptotic outcomes. PERK, IRE1α ATF6α three ER sensors activated maintain cellular proteostasis, which can also promote apoptosis prolonged stress. dual nature different types challenge researchers. We must investigate role connections among stress-associated UPR, dysfunction malignancies identify key targets prevention therapeutics.

Language: Английский

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ER-Phagy: A New Regulator of ER Homeostasis

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: July 9, 2021

The endoplasmic reticulum (ER) is one of the most important cellular organelles and essential for cell homeostasis. Upon external stimulation, ER stress induces unfolded protein response (UPR) ER-associated degradation (ERAD) to maintain However, persistent can lead damage. ER-phagy a selective form autophagy that ensures timely removal damaged ER, thereby protecting cells from damage caused by excessive stress. As newly identified autophagy, many receptor-mediated pathways have been discovered in recent years. In this review, we summarize our understanding maintenance homeostasis describe receptors date. Finally, relationships between diseases are also discussed.

Language: Английский

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Improving recombinant protein production by yeast through genome-scale modeling using proteome constraints

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: May 27, 2022

Abstract Eukaryotic cells are used as cell factories to produce and secrete multitudes of recombinant pharmaceutical proteins, including several the current top-selling drugs. Due essential role complexity secretory pathway, improvement for protein production through metabolic engineering has traditionally been relatively ad-hoc; a more systematic approach is required generate novel design principles. Here, we present proteome-constrained genome-scale model yeast Saccharomyces cerevisiae (pcSecYeast), which enables us simulate explain phenotypes caused by limited capacity. We further apply pcSecYeast predict overexpression targets proteins. experimentally validate many predicted α-amylase demonstrate application computational tool in guiding improving production.

Language: Английский

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Oxalate-induced apoptosis through ERS-ROS–NF-κB signalling pathway in renal tubular epithelial cell

Molecular Medicine, Journal Year: 2022, Volume and Issue: 28(1)

Published: Aug. 3, 2022

Abstract Background Kidney stones are composed of approximately 70–80% calcium oxalate. However, the exact mechanism formation oxalate kidney remains unclear. In this study, we investigated roles endoplasmic reticulum stress (ERS), reactive oxygen species (ROS), and NF-κB signalling pathway in pathogenesis oxalate-induced renal tubular epithelial cell injury its possible molecular mechanisms. Methods We established a model to evaluate by intraperitoneal injection glyoxylic acid solution into mice assessed morphology, apoptosis, expression levels ERS, ROS, pathway-related proteins mouse tissues. Next, treated HK-2 cells with potassium construct model. detected changes autophagy, mitochondrial membrane potential ultrastructure transmission electron microscopy. Western blotting revealed apoptosis autophagy proteins; structural functional (p65) proteins. Lastly, studied downregulation activity lentivirus interference confirmed interaction between ERS/ROS pathways. Results observed swelling tissues, increased cells, activation pathways group. found that induced damage activated ERS/ROS/NF-κB Interestingly, when was inhibited, also inhibited. Conclusion Oxalate induces through

Language: Английский

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Vascular calcification: Molecular mechanisms and therapeutic interventions

MedComm, Journal Year: 2023, Volume and Issue: 4(1)

Published: Jan. 3, 2023

Abstract Vascular calcification (VC) is recognized as a pathological vascular disorder associated with various diseases, such atherosclerosis, hypertension, aortic valve stenosis, coronary artery disease, diabetes mellitus, well chronic kidney disease. Therefore, it life‐threatening state for human health. There were several studies targeting mechanisms of VC that revealed the importance smooth muscle cells transdifferentiating, phosphorous and calcium milieu, matrix vesicles on progress VC. However, underlying molecular need to be elucidated. Though there no acknowledged effective therapeutic strategy reverse or cure clinically, recent evidence has proved not passive irreversible comorbidity but an active process regulated by many factors. Some available approaches mechanism provide promising prospects therapy This review aims summarize novel findings interventions VC, including role inflammatory responses, endoplasmic reticulum stress, mitochondrial dysfunction, iron homeostasis, metabolic imbalance, some related signaling pathways progression. We also conclude controversial in clinical practice channel blockers, renin–angiotensin system inhibitions, statins, bisphosphonates, denosumab, vitamins, ion conditioning agents.

Language: Английский

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