Hypoxia, oxidative stress, and the interplay of HIFs and NRF2 signaling in cancer

Experimental & Molecular Medicine, Год журнала: 2024, Номер 56(3), С. 501 - 514

Опубликована: Март 1, 2024

Abstract Oxygen is crucial for life and acts as the final electron acceptor in mitochondrial energy production. Cells adapt to varying oxygen levels through intricate response systems. Hypoxia-inducible factors (HIFs), including HIF-1α HIF-2α, orchestrate cellular hypoxic response, activating genes increase supply reduce expenditure. Under conditions of excess resulting oxidative stress, nuclear factor erythroid 2-related 2 (NRF2) activates hundreds oxidant removal adaptive cell survival. Hypoxia stress are core hallmarks solid tumors activated HIFs NRF2 play pivotal roles tumor growth progression. The complex interplay between hypoxia within microenvironment adds another layer intricacy HIF signaling This review aimed elucidate dynamic changes functions pathways emphasizing their implications milieu. Additionally, this explored elaborate NRF2, providing insights into significance these interactions development novel cancer treatment strategies.

Язык: 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, Год журнала: 2021, Номер 76, С. 258 - 266

Опубликована: Апрель 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.

Язык: Английский

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c-MYC-directed NRF2 drives malignant progression of head and neck cancer via glucose-6-phosphate dehydrogenase and transketolase activation

Theranostics, Год журнала: 2021, Номер 11(11), С. 5232 - 5247

Опубликована: Янв. 1, 2021

Rationale: NRF2, a redox sensitive transcription factor, is up-regulated in head and neck squamous cell carcinoma (HNSCC), however, the associated impact regulatory mechanisms remain unclear. Methods: The protein expression of NRF2 HNSCC specimens was examined by IHC. effect c-MYC on validated ChIP-qPCR, RT-qPCR western blot. impacts malignant progression were determined through genetic manipulation pharmacological inhibition vitro vivo. gene-set enrichment analysis (GSEA) data cDNA microarray combined with RT-qPCR, blot, transwell migration/ invasion, proliferation soft agar colony formation assays used to investigate NRF2. Results: positively correlated features HNSCC. In addition, carcinogens, such as nicotine arecoline, trigger c-MYC-directed activation cells. reprograms wide range cancer metabolic pathways most notable pentose phosphate pathway (PPP). Furthermore, glucose-6-phosphate dehydrogenase (G6PD) transketolase (TKT) are critical downstream effectors that drive HNSCC; coherently expressed signature NRF2/G6PD/TKT gene set potential prognostic biomarker for prediction patient overall survival. Notably, G6PD- TKT-regulated nucleotide biosynthesis more important than regulation determining Conclusions: Carcinogens activation. Over-activation promotes reprogramming TKT-mediated biosynthesis. Targeting NRF2-directed cellular metabolism an effective strategy development novel treatments cancer.

Язык: Английский

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Metabolomic profiling reveals amino acid and carnitine alterations as metabolic signatures in psoriasis

Theranostics, Год журнала: 2020, Номер 11(2), С. 754 - 767

Опубликована: Ноя. 6, 2020

High-throughput metabolite profiling provides the opportunity to reveal metabolic mechanisms and identify biomarkers.Psoriasis is an immune-mediated chronic inflammatory disease.However, role of metabolism in psoriasis pathogenesis remains unclear.Methods: Plasma samples individuals (45 45 sex-, age-, BMI-matched healthy controls) were collected.Non-targeted metabolomics amino acid-or carnitine-targeted conducted, then, plasma mice induced by imiquimod (IMQ) subjected acid-and metabolomic profiling.Flow cytometry was used study effect L-carnitine (LC(C0)) on IMQ-induced psoriatic inflammation.Results: Through non-targeted approach, we detected significantly altered acids carnitines patients.Amino acid-targeted identified 37 psoriasis, these 23 markedly upregulated, including essential (EAAs), branched-chain (BCAAs), whereas glutamine, cysteine, asparagine down-regulated.Carnitine-targeted 40 carnitines, 14 which included palmitoylcarnitine (C16) downregulated hexanoylcarnitine (C6) 3-OH-octadecenoylcarnitine (C18:1-OH) upregulated.Interestingly, asparagine, C16 levels negatively correlated with PASI score.Moreover, a higher abundance LC(C0) associated reduced epidermal thickening infiltration Th17 cells skin lesions, indicating supplementation as potential therapy for treatment.Conclusion: Our results suggested are especially EAAs, BCAAs, LC(C0), may play key roles psoriasis.

Язык: Английский

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Auranofin: Past to Present, and repurposing

International Immunopharmacology, Год журнала: 2021, Номер 101, С. 108272 - 108272

Опубликована: Окт. 29, 2021

Auranofin (AF), a gold compound, has been used to treat rheumatoid arthritis (RA) for more than 40 years; however, its mechanism of action remains unknown. We revealed that AF inhibited the induction proinflammatory proteins and their mRNAs by inflammatory stimulants, cyclooxygenase-2 inducible nitric oxide synthase, upstream regulator, NF-κB. also activated peroxyredoxin-1, Kelch-like ECH-associated protein 1, NF-E2-related factor 2, thioredoxin reductase, all which are involved in oxidative or electrophilic stress under physiological conditions. Although cell membrane was previously considered be permeable because hydrophobicity, mechanisms responsible transporting into out cells as well effects on uptake excretion other drugs have not yet elucidated. Antibodies cytokines recently employed treatment RA, had an impact use AF. Trials repurpose risk-controlled agent cancers infectious diseases, including severe acute respiratory syndrome coronavirus 2/coronavirus disease 2019, ongoing. Novel compounds development anti-cancer anti-infection agents.

Язык: Английский

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The Role of Toxic Metals and Metalloids in Nrf2 Signaling

Antioxidants, Год журнала: 2021, Номер 10(5), С. 630 - 630

Опубликована: Апрель 21, 2021

Nuclear factor erythroid 2-related 2 (Nrf2), an emerging regulator of cellular resistance to oxidants, serves as one the key defensive factors against a range pathological processes such oxidative damage, carcinogenesis, well various harmful chemicals, including metals. An increase in human exposure toxic metals via air, food, and water has been recently observed, which is mainly due anthropogenic activities. The relationship between environmental heavy metals, particularly cadmium (Cd), lead (Pb), mercury (Hg), nickel (Ni), metaloid arsenic (As), transition metal chromium (Cr), development diseases extensively investigated. Their ability induce reactive oxygen species (ROS) production through direct indirect actions cause stress documented organs. Taking into account that Nrf2 signaling represents important pathway maintaining antioxidant balance, recent research indicates it can play dual role depending on specific biological context. On side, potential crucial protective mechanism metal-induced toxicity, but other hand, also be trigger carcinogenesis under conditions prolonged continuous activation. Thus, this review aims summarize state-of-the-art knowledge regarding functional interrelation signaling.

Язык: Английский

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Epigenetics and environment in breast cancer: New paradigms for anti-cancer therapies

Frontiers in Oncology, Год журнала: 2022, Номер 12

Опубликована: Сен. 15, 2022

Breast cancer remains the most frequently diagnosed in women worldwide. Delayed presentation of disease, late stage at diagnosis, limited therapeutic options, metastasis, and relapse are major factors contributing to breast mortality. The development progression is a complex multi-step process that incorporates an accumulation several genetic epigenetic alterations. External environmental internal cellular microenvironmental cues influence occurrence these alterations drives tumorigenesis. Here, we discuss state-of-the-art information on epigenetics how risk orchestrate events, emphasizing necessity for multidisciplinary approach toward better understanding gene-environment interactions implicated cancer. Since modifications reversible susceptible extrinsic intrinsic stimuli, they offer potential avenues can be targeted designing robust therapies.

Язык: Английский

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Endoplasmic reticulum stress responses and epigenetic alterations in arsenic carcinogenesis

Environmental Pollution, Год журнала: 2024, Номер 347, С. 123565 - 123565

Опубликована: Фев. 17, 2024

Arsenic is a well-known human carcinogen whose environmental exposure via drinking water, food, and air impacts millions of people across the globe. Various mechanisms arsenic carcinogenesis have been identified, ranging from damage caused by excessive production free radicals epigenetic alterations to generation cancer stem cells. A growing body evidence supports critical involvement endoplasmic stress-activated unfolded protein response (UPR) in promoting as well suppressing development/progression. vitro vivo models also demonstrated that induces UPR activation PERK, IRE1α, ATF6 proteins. In this review, we discuss arsenic-induced reticulum stress role each pathway various types with focus on regulation function protein. The importance cells relatively new area research requires additional investigations omics-based computational tools. These approaches will provide interesting insights into cancers for prospective target identification development novel anti-cancer therapies.

Язык: Английский

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Health Effects Associated With Pre- and Perinatal Exposure to Arsenic

Frontiers in Genetics, Год журнала: 2021, Номер 12

Опубликована: Сен. 29, 2021

Inorganic arsenic is a well-established human carcinogen, able to induce genetic and epigenetic alterations. More than 200 million people worldwide are exposed concentrations in drinking water exceeding the recommended WHO threshold (10μg/l). Additionally, chronic exposure levels below this known result long-term health effects humans. The arsenic-related humans associated with its biotransformation process, whereby resulting metabolites can molecular damage that accumulates over time. derived from these alterations include genomic instability oxidative damage, alteration of gene expression (including coding non-coding RNAs), global localized reprogramming, histone posttranslational modifications. These directly affect pathways involved onset progression many conditions arise even decades after occurs. Importantly, generated during also pass through placental barrier, fetal carcinogen at similar those mother. As such, more immediate arsenic-induced be observed as detrimental on development, pregnancy, birth outcomes. In review, we focus low arsenic, particularly affecting early developmental stages. We present how occurring life impact development certain diseases adult life.

Язык: Английский

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The role of hypoxia-inducible factor 1 alpha (HIF-1α) modulation in heavy metal toxicity

Archives of Toxicology, Год журнала: 2023, Номер 97(5), С. 1299 - 1318

Опубликована: Март 18, 2023

Язык: Английский

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