Redox‐sensitive signaling pathways in renal cell carcinoma

Cruz-Gregorio, Alfredo; Aranda-Rivera, Ana Karina; Pedraza‐Chaverrí, José; Solano, José D.; Ibarra-Rubio, María Elena

doi:10.1002/biof.1784

Cited by 8 publications

(2 citation statements)

References 173 publications

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“…The parallel decline suggests that increased stress from excess iA␤ is just one of many possible age-related stressors possibly associated with inflammation. Oxidative redox stress is well known to alter signaling through sensitivity to dimerization of growth factor receptors, NfkB and Akt signaling (e.g., [99,100]) and possibly A␤PP processing [101]. We did not see evidence of circadian oscillation, possibly related to tighter control of redox state in the brain compared to plasma.…”

Section: Glutathione and Redox Statecontrasting

confidence: 60%

Age-Related Oxidative Redox and Metabolic Changes Precede Intraneuronal Amyloid-β Accumulation and Plaque Deposition in a Transgenic Alzheimer’s Disease Mouse Model

Pontrello

McWhirt

Glabe

et al. 2022

JAD

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Background: Many identified mechanisms could be upstream of the prominent amyloid-β (Aβ) plaques in Alzheimer’s disease (AD). Objective: To profile the progression of pathology in AD. Methods: We monitored metabolic signaling, redox stress, intraneuronal amyloid-β (iAβ) accumulation, and extracellular plaque deposition in the brains of 3xTg-AD mice across the lifespan. Results: Intracellular accumulation of aggregated Aβ in the CA1 pyramidal cells at 9 months preceded extracellular plaques that first presented in the CA1 at 16 months of age. In biochemical assays, brain glutathione (GSH) declined with age in both 3xTg-AD and non-transgenic controls, but the decline was accelerated in 3xTg-AD brains from 2 to 4 months. The decline in GSH correlated exponentially with the rise in iAβ. Integrated metabolic signaling as the ratio of phospho-Akt (pAkt) to total Akt (tAkt) in the PI3kinase and mTOR pathway declined at 6, 9, and 12 months, before rising at 16 and 20 months. These pAkt/tAkt ratios correlated with both iAβ and GSH levels in a U-shaped relationship. Selective vulnerability of age-related AD-genotype-specific pAkt changes was greatest in the CA1 pyramidal cell layer. To demonstrate redox causation, iAβ accumulation was lowered in cultured middle-age adult 3xTg-AD neurons by treatment of the oxidized redox state in the neurons with exogenous cysteine. Conclusion: The order of pathologic progression in the 3xTg-AD mouse was loss of GSH (oxidative redox shift) followed by an pAkt/tAkt metabolic shift in CA1, iAβ accumulation in CA1, and extracellular Aβ deposition. Upstream targets may prove strategically more effective for therapy before irreversible changes.

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Section: Glutathione and Redox Statecontrasting

confidence: 60%

Age-Related Oxidative Redox and Metabolic Changes Precede Intraneuronal Amyloid-β Accumulation and Plaque Deposition in a Transgenic Alzheimer’s Disease Mouse Model

Pontrello

McWhirt

Glabe

et al. 2022

JAD

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“…The redox state of cellular is determined by the ratio of antioxidants to oxidants (34). Antioxidants include the enzymes SOD, glutathione peroxidase (GPx), and CAT, and nonenzymes such as GSH and vitamins A, C, and E. Oxidants include ROS such as hydrogen peroxide (H 2 O 2 ), superoxide anion radical (O2 •− ), and hydroxyl radical ( • OH) (35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

Melatonin induces cell apoptosis in renal carcinoma cells via regulating mitochondria function, promoting ROS production, and suppression of Akt/mTOR/S6K signaling pathway

Ke-min

Jiang

Bai

et al. 2023

Preprint

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Purpose In recent years, metabolic alteration has been identified as a driver in the development of renal cell carcinoma (RCC), which plays a critical role in cancer cells to adapt to hypoxic environment and cell proliferation. Melatonin (MLT), a neurohormone secreted during the dark hours by the vertebrate pineal gland, induces metabolic reprogramming in cancer cells by suppression of aerobic glycolysis. Whether it can be used as a potential therapeutic tool in RCC is worth exploring. Methods In this study, we detected concentration of metabolites in RCC cells through metabo-lomic analyses using UPLC-MS/MS and the oxygen consumption rate was determined using the Seahorse Extracellular Flux analyzer. Results We found that MLT significantly inhibited proliferation and induced apoptosis in RCC cells, moreover, MLT increased ROS level and inhibited the activity of antioxidant enzymes. Furthermore, MLT up-regulated key TCA cycle metabolites while reduced aerobic glycolysis products, and induced higher oxygen consumption rate, more ATP production, and higher membrane potential in RCC cells, indicating that MLT enhances mitochondrial function and re-vert aerobic glycolysis to mitochondrial OXPHOS in RCC cells. Moreover, MLT treatment inhibited the phosphorylation levels of Akt, mTOR, and p70 S6 Kinase in RCC cells, while the application of NAC (inhibitors of ROS) not only restored the phosphorylation of these proteins but also decreased cell apoptosis. Consistently, MLT treatment significantly inhibited growth of RCC cell xenografts in nude mice. Conclusion Our results indicate that MLT treatment promotes intracellular ROS production via metabolic reprogramming and reducing antioxidants, which suppressed the activity of Akt/mTOR/S6K signaling pathway and induced apoptosis in RCC cells.

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Design, synthesis and molecular docking of novel substituted azepines as inhibitors of PI3K/Akt/TSC2/mTOR signaling pathway in colorectal carcinoma

Noser

Abdelmonsef

Salem

2023

Bioorganic Chemistry

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Redox‐sensitive signaling pathways in renal cell carcinoma

Cited by 8 publications

References 173 publications

Age-Related Oxidative Redox and Metabolic Changes Precede Intraneuronal Amyloid-β Accumulation and Plaque Deposition in a Transgenic Alzheimer’s Disease Mouse Model

Age-Related Oxidative Redox and Metabolic Changes Precede Intraneuronal Amyloid-β Accumulation and Plaque Deposition in a Transgenic Alzheimer’s Disease Mouse Model

Melatonin induces cell apoptosis in renal carcinoma cells via regulating mitochondria function, promoting ROS production, and suppression of Akt/mTOR/S6K signaling pathway

Design, synthesis and molecular docking of novel substituted azepines as inhibitors of PI3K/Akt/TSC2/mTOR signaling pathway in colorectal carcinoma

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