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NRF2: A crucial regulator for mitochondrial metabolic shift and prostate cancer progression.

Metabolic alterations are a common survival mechanism for prostate cancer progression and therapy resistance. Oxidative stress in the cellular and tumor microenvironment dictates metabolic switching in the cancer cells to adopt, prosper and escape therapeutic stress. Therefore, regulation of oxidative stress in tumor cells and in the tumor-microenvironment may enhance the action of conventional anticancer therapies. NRF2 is the master regulator for oxidative stress management. However, the overall oxidative stress varies with PCa clinical stage, metabolic state and therapy used for the cancer.

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… The major rate limiting enzymes of the pentose phosphate pathway, G6PD and 6PGD, are target genes of NRF2 ( Hagiwara et al., 2021 ). … However, glutathione oxidation is a crucial metabolic regulator of the pentose phosphate pathway ( Amara et al., 2020 ). Levels of NAD and NADPH regulate overall oxidative stress and metabolic shifts in PCa. …

High-dose intravenous vitamin C, a promising multi-targeting agent in the treatment of cancer.

Mounting evidence indicates that vitamin C has the potential to be a potent anti-cancer agent when administered intravenously and in high doses (high-dose IVC). Early phase clinical trials have confirmed safety and indicated efficacy of IVC in eradicating tumour cells of various cancer types. In recent years, the multi-targeting effects of vitamin C were unravelled, demonstrating a role as cancer-specific, pro-oxidative cytotoxic agent, anti-cancer epigenetic regulator and immune modulator, reversing epithelial-to-mesenchymal transition, inhibiting hypoxia and oncogenic kinase signalling and b

Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target.

In order to meet the high energy demand, a metabolic reprogramming occurs in cancer cells. Its role is crucial in promoting tumor survival. Among the substrates in demand, oxygen is fundamental for bioenergetics. Nevertheless, tumor microenvironment is frequently characterized by low-oxygen conditions. Hypoxia-inducible factor 1 (HIF-1) is a pivotal modulator of the metabolic reprogramming which takes place in hypoxic cancer cells. In the hub of cellular bioenergetics, mitochondria are key players in regulating cellular energy. Therefore, a close crosstalk between mitochondria and HIF-1 underl

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… In the context of glucose metabolism reprogramming in hypoxia, the pentose phosphate pathway activity also decreases due to a reduced expression of glucose-6-phosphate dehydrogenase. As a consequence, synthesis of nucleotides and cell proliferation are affected. … Metabolic changes associated with tumor metastasis, Part 1: Tumor pH, glycolysis and the pentose phosphate pathway Cell. Mol. Life Sci. 2016 73 1333 1348 10.1007/s00018-015-2098-5 26626411 PMC11108399 6. Fearon K.C. Glass D.J. Guttridge D.C. …

Метаболомическое исследование синдромов миэлодипластика, множественной миеломы и гомозиговой β-Талассемии.

Хроническая анемия, как правило, диагностируется у пожилых людей и служит важным показателем как реактивных, так и клональных заболеваний. Многие основные заболевания, такие, как миэллодипластические синдромы и множественная миелома, более распространены среди пожилых людей, в то время как новые терапевтические подходы превратили педиатрические расстройства слабого прогноза, такие, как бета-талассемия, в хроническое заболевание пожилых людей. Таким образом, растущая распространенность хронической анемии в пожилом возрасте в значительной степени объясняется более частыми диагностическими и тера

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… Interestingly, pathways typically altered in anemia (mainly glycolysis and the pentose phosphate pathway) were not directly implicated in β-thalassemia based on the results of this study, suggesting that the impacted pathways are more specific to disease complications, which significantly increase with … On the other hand, ATP levels in RBCs from β-thalassemia major are significantly reduced, suggesting a shift in glucose metabolism away from glycolysis and towards the pentose phosphate pathway, likely as a response to oxidative stress [ 184 ]. …

Targeting Glutathione Metabolism: Partner in Crime in Anticancer Therapy.

Glutathione (GSH) is the predominant low-molecular-weight antioxidant with a ubiquitous distribution inside the cell. The steady-state level of cellular GSH is dependent on the balance between synthesis, hydrolysis, recycling of glutathione disulphide (GSSG) as well as cellular extrusion of reduced, oxidized, or conjugated-forms. The augmented oxidative stress typical of cancer cells is accompanied by an increase of glutathione levels that confers them growth advantage and resistance to a number of chemotherapeutic agents. Targeting glutathione metabolism has been widely investigated for cance

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… Accumulation of GSSG is potentially toxic for the cell, as it acts as a pro-oxidant, and it is promptly reduced back to GSH by glutathione reductase (GR) using NADPH, which is mainly produced by the oxidative branch of the pentose phosphate pathway (PPP) [ 2 , 3 ]. …

Targeting Metabolic Reprogramming in Acute Myeloid Leukemia.

The cancer metabolic reprogramming allows the maintenance of tumor proliferation, expansion and survival by altering key bioenergetics, biosynthetic and redox functions to meet the higher demands of tumor cells. In addition, several metabolites are also needed to perform signaling functions that further promote tumor growth and progression. These metabolic alterations have been exploited in different cancers, including acute myeloid leukemia, as novel therapeutic strategies both in preclinical models and clinical trials. Here, we review the complexity of acute myeloid leukemia (AML) metabolism

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… PPP—pentose phosphate pathway; IDH1,2/3—Isocitrate dehydrogenase 1,2/3; GLS—glutaminase; GLUD—glutamate dehydrogenase; GLUTs—glucose transporters; MCTs—monocarboxylate transporters; OXPHOS—Oxidative Phosphorylation. 2.1. … The high glycolytic rate with concomitant ATP production requires the availability of precursors for anabolic pathways, such as intermediates of the tricarboxylic acid (TCA) cycle and the pentose phosphate pathway (PPP) ( Figure 1 ). …

Р

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Circadian clock and cancer.

Circadian rhythms play a critical role in regulating physiological and behavioral processes, such as the sleep-wake cycle, hormone secretion, and metabolism. These rhythms are controlled by endogenous biological clocks, which are synchronized with environmental cues, primarily the light-dark cycle. Notably, disruption or reprogramming of circadian rhythms is closely associated with cancer initiation, progression, and treatment response. At the molecular level, the dysregulation of core clock genes can disturb normal cellular rhythms, leading to aberrant cell proliferation, impaired DNA repair,

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… BMAL1, for instance, regulates the rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD) in the pentose phosphate pathway (PPP) to maintain nucleotide pools and prevent replication stress [83] . …

Noncanonical SQSTM1/p62-Nrf2 pathway activation mediates proteasome inhibitor resistance in multiple myeloma cells via redox, metabolic and translational reprogramming.

Multiple Myeloma (MM) is a B-cell malignancy characterized by the accumulation of clonal plasma cells in the bone marrow, with drug resistance being a major cause of therapeutic failure. We established a carfilzomib-resistant derivative of the LP-1 MM cell line (LP-1/Cfz) and found that the transcription factor NF-E2 p45-related factor 2 (Nrf2; gene symbol NFE2L2) contributes to carfilzomib resistance. The mechanism of Nrf2 activation involved enhanced translation of Nrf2 as well as its positive regulator, the autophagy receptor sequestosome 1 (SQSTM1)/p62. The eukaryotic translation initiatio

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… Specifically, Nrf2 facilitates NADPH production by directing carbon flux through the pentose phosphate pathway [ 56 ]. … Consistent with the hypothesis that Nrf2 is activated in LP-1/Cfz as well as in KMS-11/Cfz cells, NADPH levels were increased concomitant with upregulation of KEGG pentose phosphate pathway genes in both models ( Figure S6 ). …

Lactylation in health and disease: physiological or pathological?

Lactate is an indispensable substance in various cellular physiological functions and plays regulatory roles in different aspects of energy metabolism and signal transduction. Lactylation (Kla), a key pathway through which lactate exerts its functions, has been identified as a novel posttranslational modification (PTM). Research indicates that Kla is an essential balancing mechanism in a variety of organisms and is involved in many key cellular biological processes through different pathways. Kla is closely related to disease development and represents a potential and important new drug target

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… phosphate pathway (PPP) to promote cervical cancer progression; | PMID: 38291438 MRE11 | K673 | Promote its binding to DNA and promote DNA end resection and homologous recombination; | PMID: 38128537 AMPKα | unknown | Unknown; | PMID: 38486093 Snail1 | unknown | RHOF overexpression promotes the lactylation … Meng et al. demonstrated that the HPV16 E6 protein enhances cervical cancer cell proliferation by activating the pentose phosphate pathway (PPP) and suppressing the Kla of G6PD dimers 140 . …

Keyword Index for Volume 91

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Metabolic reprogramming in cancer and senescence.

The rising trend in global cancer incidence has caused widespread concern, one of the main reasons being the aging of the global population. Statistical data show that cancer incidence and mortality rates show a clear upward trend with age. Although there is a commonality between dysregulated nutrient sensing, which is one of the main features of aging, and metabolic reprogramming of tumor cells, the specific regulatory relationship is not clear. This manuscript intends to comprehensively analyze the relationship between senescence and tumor metabolic reprogramming; as well as reveal the impac

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… The main characteristics of tumor metabolic reprogramming are glycolysis, protein decomposition, lipid metabolism, mitochondrial biogenesis, pentose phosphate pathway, and other biosynthesis and bioenergy pathway upregulation. … Glucose is the most important energy‐supplying substance in the organism, and its metabolic pathway is mainly divided into glycolysis pathway, pentose phosphate pathway, and oxidative phosphorylation. …

IDH Mutations in Glioma: Molecular, Cellular, Diagnostic, and Clinical Implications.

In 2021, the World Health Organization classified isocitrate dehydrogenase (IDH) mutant gliomas as a distinct subgroup of tumors with genetic changes sufficient to enable a complete diagnosis. Patients with an IDH mutant glioma have improved survival which has been further enhanced by the advent of targeted therapies. IDH enzymes contribute to cellular metabolism, and mutations to specific catalytic residues result in the neomorphic production of D-2-hydroxyglutarate (D-2-HG). The accumulation of D-2-HG results in epigenetic alterations, oncogenesis and impacts the tumor microenvironment via i

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… The oxidative pentose phosphate pathway is recognized as the major producer of cytosolic NADPH. NADPH is primarily used for fatty acid biosynthesis and to maintain the cellular pool of reduced glutathione for mitigating ROS. … This leads to an increase in the cellular demand for NADPH, amplifying flux through the NADPH-producing pentose phosphate pathway. Interestingly, both IDH1 -R132H mutants and IDH2 -R172K mutants are more susceptible to oxidative insults. …

Dual Roles of NIX/BNIP3L in Tumors: Friend or Foe.

Cancer is one of the leading causes of disease-related death worldwide, and targeting key regulatory genes to induce programmed cell death in tumor cells has emerged as a crucial therapeutic strategy, following surgery, radiotherapy, and chemotherapy. As a mitochondrial outer membrane protein, NIX/BNIP3L can both mediate apoptosis to inhibit tumor cell growth and promote tumor cell survival by clearing intracellular reactive oxygen species (ROS) through mitophagy. Therefore, we summarize a brief overview of the structure and function of NIX/BNIP3L, as well as the mechanisms of NIX/BNIP3L gener

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… Concurrently, this metabolic shift suppresses aerobic oxidation and redirects flux predominantly through the non-oxidative phase of the pentose phosphate pathway (PPP). This reprogramming maintains the NADPH/NADP + ratio [ 87 ], ultimately stabilizing intracellular redox homeostasis. … Overexpressed NIX reprograms the energy metabolism of cancer cells through mitophagy, maintaining the NADPH/NADP + ratio via the pentose phosphate pathway. …

Изучение связи между 91 циркуляцией воспламенительных протеинов и нейродегенеративными заболеваниями: двухнаправленный анализ менделей и биоинформатики.

Циркуляция подстрекательских белков играет важную роль в патогенезе нейродегенеративных заболеваний (НДД). Однако точная причинно-следственная связь и механизмы, лежащие в основе их взаимодействия, по-прежнему остаются неясными. МЕТОДЫ: В каталоге GWAS были получены данные по 91 циркуляционному подстрекательскому протеину в рамках исследования ассоциации геномов (GWAS). Кроме того, данные GWAS о болезни Паркинсона (PD), болезни Альцгеймера (AD), амиотропическом боковом склерозе (ALS), множественном склерозе (MS) и ишемическом инсульте (IS) были получены в рамках проекта IEU Open GWAS. Для анал

Oleocanthal as a Multifunctional Anti-Cancer Agent: Mechanistic Insights, Advanced Delivery Strategies, and Synergies for Precision Oncology.

Oleocanthal (OC), a secoiridoid phenolic compound exclusive to extra virgin olive oil (EVOO), has emerged as a promising nutraceutical with multifaceted anti-cancer properties. Despite its well-characterized anti-inflammatory and antioxidant effects, the mechanistic breadth and translational potential of OC in oncology remain underexplored and fragmented across the literature. This comprehensive review synthesizes and critically analyzes recent advances in the molecular, pharmacological, and translational landscape of OC's anti-cancer activities, providing an integrative framework to bridge pr

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… Section 8 (Oleocanthal as a Modulator of Metabolic Programming and Tumor Bioenergetics) : This section investigates OC’s emerging role in regulating cancer cell metabolism, including its potential effects on the Warburg effect, mitochondrial function, the pentose phosphate pathway (PPP), and lipid metabolism …

LncRNA NEAT1 restrains the malignant biological characteristics of acute myeloid leukemia via regulating CTCF/CXCR2 axis.

Acute myeloid leukemia (AML) is notorious in the field of hematology for its poor efficacy, frustrating prognosis, and it is prone to refractory or relapsed conditions. Previous studies in our team have shown that some Long noncoding RNAs (lncRNAs) and chemokine receptors play key regulatory roles in AML. The findings of this study demonstrated that the expression of NEAT1 was atypically low in both clinical AML specimens and AML cell lines. Overexpression of NEAT1 was capable of attenuating the malignant biological characteristics of AML cells, including inhibiting the malignant proliferation

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… Gu H Chen C Hou ZS PI3Kγ maintains the self-renewal of acute myeloid leukemia stem cells by regulating the Pentose phosphate pathway Blood 2024 143 19 1965 79 10.1182/blood.2023022202 38271660 PMC11103183 Gu H, Chen C, Hou ZS, et al. … PI3Kγ maintains the self-renewal of acute myeloid leukemia stem cells by regulating the Pentose phosphate pathway. Blood. 2024;143(19):1965–79. 10.1182/blood.2023022202. 38271660 10.1182/blood.2023022202 PMC11103183 67. …

Metabolic Rewiring in Radiation Oncology Toward Improving the Therapeutic Ratio.

To meet the anabolic demands of the proliferative potential of tumor cells, malignant cells tend to rewire their metabolic pathways. Although different types of malignant cells share this phenomenon, there is a large intracellular variability how these metabolic patterns are altered. Fortunately, differences in metabolic patterns between normal tissue and malignant cells can be exploited to increase the therapeutic ratio. Modulation of cellular metabolism to improve treatment outcome is an emerging field proposing a variety of promising strategies in primary tumor and metastatic lesion treatme

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… A balanced exit of glycolytic intermediates ensures that the anabolic pathways are constantly replenished and (intermediate) products are transferred to the pentose‑phosphate-pathway (PPP), fatty acid (FA) synthesis and tricarboxylic acid (TCA) cycle in order to meet tumor’s metabolic need to proliferate … Lonidamine also inhibits malate and fumarate formation in the citric acid cycle and it influences the ETC function by disturbing the mitochondrial transmembrane potential through inhibition of Complex II (CII) and the pentose phosphate pathway causing a decreased NADPH and glutathione pool ( 42 , 282 …

Nutritional approaches in combating therapeutic resistance and enhancing treatment efficacy in cancer: the impact of ketogenic diets.

Cancer remains a major global health challenge, with therapeutic resistance significantly limiting treatment success. Traditional approaches, including surgery, chemotherapy, and radiotherapy, often encounter barriers such as metastasis and adverse effects on healthy tissues. The Warburg effect, which describes cancer cells’ reliance on glucose fermentation despite oxygen availability, has prompted investigations into alternative metabolic interventions. The ketogenic diet (KD), characterized by high fat intake and low carbohydrate intake, induces a metabolic shift that may selectively disadva

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… Research has demonstrated that bortezomib-resistant cells in multiple myeloma redirect glucose toward the pentose phosphate pathway and serine synthesis pathway, enhancing their antioxidant capabilities. The PPP generates NADPH, helping maintain GSH levels and cellular redox equilibrium. … Research on sorafenib-resistant leukemia cells revealed increased glucose requirements and reduced pentose phosphate pathway (PPP) activity [ 62 ]. Studies on imatinib-resistant CML cells have yielded conflicting results. …

Drug Repurposing Approaches towards Defeating Multidrug-Resistant Gram-Negative Pathogens: Novel Polymyxin/Non-Antibiotic Combinations.

Multidrug-resistant (MDR) Gram-negative pathogens remain an unmet public health threat. In recent times, increased rates of resistance have been reported not only to commonly used antibiotics, but also to the last-resort antibiotics, such as polymyxins. More worryingly, despite the current trends in resistance, there is a lack of new antibiotics in the drug-discovery pipeline. Hence, it is imperative that new strategies are developed to preserve the clinical efficacy of the current antibiotics, particularly the last-line agents. Combining conventional antibiotics such as polymyxins with non-an

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… Moreover, it was inferred from metabolomics analysis of A. baumannii ATCC™ 19606 that the polymyxin B/cannabidiol combination substantially disrupts cell envelope biogenesis through a time-dependent perturbation of amino–sugar and nucleotide–sugar metabolism, and the pentose phosphate pathway. …