Revisiting the Warburg effect: historical dogma versus current understanding

The Journal of Physiology, Journal Year: 2020, Volume and Issue: 599(6), P. 1745 - 1757

Published: Dec. 22, 2020

Abstract Contrary to Warburg's original thesis, accelerated aerobic glycolysis is not a primary, permanent and universal consequence of dysfunctional or impaired mitochondria compensating for poor ATP yield per mole glucose. Instead, in most tumours the Warburg effect an essential part ‘selfish’ metabolic reprogramming, which results from interplay between (normoxic/hypoxic) hypoxia‐inducible factor‐1 (HIF‐1) overexpression, oncogene activation (cMyc, Ras), loss function tumour suppressors (mutant p53, mutant phosphatase tensin homologue (PTEN), microRNAs sirtuins with suppressor functions), activated (PI3K–Akt–mTORC1, Ras–Raf–MEK–ERK–cMyc, Jak–Stat3) deactivated (LKB1–AMPK) signalling pathways, components microenvironment, HIF‐1 cooperation epigenetic mechanisms. Molecular functional processes include: (a) considerable acceleration glycolytic fluxes; (b) adequate generation unit time maintain energy homeostasis electrochemical gradients; (c) backup diversion intermediates facilitating biosynthesis nucleotides, non‐essential amino acids, lipids hexosamines; (d) inhibition pyruvate entry into mitochondria; (e) excessive formation accumulation lactate, stimulates growth suppression anti‐tumour immunity – addition, lactate can serve as source normoxic cancer cells drives malignant progression resistances conventional therapies; (f) cytosolic being mainly exported through upregulated lactate–proton symporters (MCT4), working together other H + transporters, carbonic anhydrases (CAII, CAIX), hydrate CO 2 oxidative metabolism form bicarbonate; (g) these proton export mechanisms, concert vascular drainage, responsible extracellular acidification, driving resistance (h) maintenance cellular redox low reactive oxygen species (ROS) formation; (i) p53 PTEN, inhibit mitochondrial biogenesis functions, negatively impacting respiration rate. The switch early event oncogenesis primarily supports cell survival. All all, effect, i.e. presence principle functioning mitochondria, constitutes major driver machinery, therapies, patient outcome. However, evidenced during last two decades, minority primary defects play key role promoting due mutations some Krebs cycle enzymes ROS overproduction. image

Language: Английский

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Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation

Cells, Journal Year: 2021, Volume and Issue: 10(5), P. 1056 - 1056

Published: April 29, 2021

Cancer cells alter metabolic processes to sustain their characteristic uncontrolled growth and proliferation. These alterations include (1) a shift from oxidative phosphorylation aerobic glycolysis support the increased need for ATP, (2) glutaminolysis NADPH regeneration, (3) altered flux through pentose phosphate pathway tricarboxylic acid cycle macromolecule generation, (4) lipid uptake, lipogenesis, cholesterol synthesis, (5) upregulation of one-carbon metabolism production NADH/NADPH, nucleotides, glutathione, (6) amino metabolism, (7) metabolism-based regulation apoptosis, (8) utilization alternative substrates, such as lactate acetate. Altered in cancer is controlled by tumor-host cell interactions, key oncogenes, tumor suppressors, other regulatory molecules, including non-coding RNAs. Changes pathways are dynamic, exhibit plasticity, often dependent on type microenvironment, leading thought Warburg Effect "reverse Effect" plasticity. Understanding complex nature these multiple can development new therapies.

Language: Английский

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The Potential of Metabolomics in Biomedical Applications

Metabolites, Journal Year: 2022, Volume and Issue: 12(2), P. 194 - 194

Published: Feb. 19, 2022

The metabolome offers a dynamic, comprehensive, and precise picture of the phenotype. Current high-throughput technologies have allowed discovery relevant metabolites that characterize wide variety human phenotypes with respect to health, disease, drug monitoring, even aging. Metabolomics, parallel genomics, has led biomarkers aided in understanding diversity molecular mechanisms, highlighting its application precision medicine. This review focuses on metabolomics can be applied improve as well trends impacts metabolic neurodegenerative diseases, cancer, longevity, exposome, liquid biopsy development, pharmacometabolomics. identification distinct metabolomic profiles will help improvement clinical strategies treat disease. In years come, become tool routinely diagnose monitor health aging, or development. Biomedical applications already foreseen progression such obesity diabetes, using branched-chain amino acids, acylcarnitines, certain phospholipids, genomics; these assess disease severity predict potential treatment. Future endeavors should focus determining applicability utility metabolomic-derived markers their appropriate implementation large-scale settings.

Language: Английский

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To metabolomics and beyond: a technological portfolio to investigate cancer metabolism

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: March 22, 2023

Abstract Tumour cells have exquisite flexibility in reprogramming their metabolism order to support tumour initiation, progression, metastasis and resistance therapies. These reprogrammed activities include a complete rewiring of the bioenergetic, biosynthetic redox status sustain increased energetic demand cells. Over last decades, cancer field has seen an explosion new biochemical technologies giving more tools than ever before navigate this complexity. Within cell or tissue, metabolites constitute direct signature molecular phenotype thus profiling concrete clinical applications oncology. Metabolomics fluxomics, are key technological approaches that mainly revolutionized enabling researchers both qualitative mechanistic model cancer. Furthermore, upgrade from bulk single-cell analysis provided unprecedented opportunity investigate biology at cellular resolution allowing depth quantitative complex heterogenous diseases. More recently, advent functional genomic screening allowed identification pathways, processes, biomarkers novel therapeutic targets concert with other allow patient stratification treatment regimens. This review is intended be guide for metabolism, highlighting current emerging technologies, emphasizing advantages, disadvantages potential leading development innovative anti-cancer

Language: Английский

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CircXRN2 suppresses tumor progression driven by histone lactylation through activating the Hippo pathway in human bladder cancer

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Sept. 8, 2023

Bladder cancer (BCa) is the fourth most common malignant tumor with a poor prognosis worldwide. Further exploration and research are needed to unmask underlying roles molecular mechanisms of circular RNAs. In current study, our findings showed that circXRN2 suppresses progression driven by histone lactylation activating Hippo pathway in human bladder cancer.RNA immunoprecipitation (RIP) followed circRNA sequencing confirmed as object. Overexpression knockdown TAZ/YAP further verified biological functions T24 TCCSUP cells. RIP, coimmunoprecipitation were used elucidate interaction between LATS1. A Seahorse metabolic analyzer was determine glycolytic rate. Cleavage under targets Tagmentation (CUT&Tag) chromatin (ChIP) employed ensure regulatory H3K18 transcriptional activity LCN2.CircXRN2 aberrantly downregulated tissues cell lines. CircXRN2 inhibits proliferation migration cells both vitro vivo. addition, serves negative regulator glycolysis lactate production. Mechanistically, prevents LATS1 from SPOP-mediated degradation binding SPOP degron then activates signaling exert various functions. The circXRN2-Hippo axis modulates inhibiting LCN2 expression cancer.CircXRN2 cancer. Our results indicated novel therapeutic provided promising strategies for clinical intervention

Language: Английский

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Sunitinib resistance in renal cell carcinoma: From molecular mechanisms to predictive biomarkers

Drug Resistance Updates, Journal Year: 2023, Volume and Issue: 67, P. 100929 - 100929

Published: Jan. 17, 2023

Currently, renal cell carcinoma (RCC) is the most prevalent type of kidney cancer. Targeted therapy has replaced radiation and chemotherapy as main treatment option for RCC due to lack significant efficacy with these conventional therapeutic regimens. Sunitinib, a drug used treat gastrointestinal tumors carcinoma, inhibits tyrosine kinase activity number receptor kinases, including vascular endothelial growth factor (VEGFR), platelet-derived (PDGFR), c-Kit, rearranged during transfection (RET) fms-related 3 (Flt3). Although sunitinib been shown be efficacious in patients advanced RCC, have primary resistance or acquired within 6–15 months therapy. Thus, order develop more long-lasting strategies it will crucial ascertain how overcome that produced by various mechanisms. In this review, we discuss: 1) molecular mechanisms resistance; 2) 3) potential predictive biomarkers resistance.

Language: Английский

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Nuclear genome-derived circular RNA circPUM1 localizes in mitochondria and regulates oxidative phosphorylation in esophageal squamous cell carcinoma

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Feb. 14, 2022

Abstract Circular RNAs (circRNAs) were shown to play an important role in the occurrence and progression of tumors. However, functions nuclear genome-derived circRNAs localized mitochondria tumor cells remain largely elusive. Here, we report that circPUM1, a circular RNA derived from back-splicing pre-mRNAs genome PUM1, localizes mitochondria. The expression level circPUM1 is positively correlated with HIF1α accumulation under CoCl 2 -induced intracellular hypoxic-like condition esophageal squamous cell carcinoma (ESCC) lines. Importantly, acts as scaffold for interaction between UQCRC1 UQCRC2 ESCC Knock-down would result lower oxygen concentration, downregulated oxidative phosphorylation, decrease mitochondrial membrane potential, increase ROS generation shrinking mitochondria, respectively. CircPUM1 depletion induces dysfunction complex III cleavage caspase3 spontaneously. Interestingly, disruption led pyroptosis initiates death Therefore, conclude plays critical maintaining stability enhance phosphorylation ATP production moreover propose exploit during adaptation.

Language: Английский

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In Response to Precision Medicine: Current Subcellular Targeting Strategies for Cancer Therapy

Advanced Materials, Journal Year: 2022, Volume and Issue: 35(21)

Published: Nov. 29, 2022

Abstract Emerging as a potent anticancer treatment, subcellular targeted cancer therapy has drawn increasing attention, bringing great opportunities for clinical application. Here, two targeting strategies four main organelles (mitochondria, lysosome, endoplasmic reticulum, and nucleus), including molecule‐ nanomaterial (inorganic nanoparticles, micelles, organic polymers, others)‐based delivery or therapeutic strategies, are summarized. Phototherapy, chemotherapy, radiotherapy, immunotherapy, “all‐in‐one” combination among the covered in detail. Such materials constructed based on specific properties relevant mechanisms of organelles, enabling elimination tumors by inducing dysfunction corresponding destroying structures. The challenges faced organelle‐targeting therapies also Looking forward, paradigm with enhanced efficacy compared to current approaches is envisioned.

Language: Английский

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Liquid Biopsies, Novel Approaches and Future Directions

Cancers, Journal Year: 2023, Volume and Issue: 15(5), P. 1579 - 1579

Published: March 3, 2023

Cancer is among the leading causes of death worldwide. Early diagnosis and prognosis are vital to improve patients’ outcomes. The gold standard tumor characterization tissue biopsy. Amongst constraints biopsy collection sampling frequency incomplete representation entire bulk. Liquid approaches, including analysis circulating cells (CTCs), DNA (ctDNA), miRNAs, tumor-derived extracellular vesicles (EVs), as well certain protein signatures that released in circulation from primary tumors their metastatic sites, present a promising more potent candidate for patient follow up monitoring. minimally invasive nature liquid biopsies, allowing frequent collection, can be used monitoring therapy response real time, development novel approaches therapeutic management cancer patients. In this review we will describe recent advances field markers focusing on advantages disadvantages.

Language: Английский

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Recent advances and clinical translation of liposomal delivery systems in cancer therapy

European Journal of Pharmaceutical Sciences, Journal Year: 2024, Volume and Issue: 193, P. 106688 - 106688

Published: Jan. 1, 2024

The limitations of conventional cancer treatment are driving the emergence and development nanomedicines. Research in liposomal nanomedicine for therapy is rapidly increasing, opening up new horizons treatment. Liposomal nanomedicine, which focuses on targeted drug delivery to improve therapeutic effect while reducing damage normal tissues cells, has great potential field therapy. This review aims clarify advantages systems We describe recent understanding spatiotemporal fate liposomes organism after different routes administration. Meanwhile, various types liposome-based that exert their respective side effects were discussed. Moreover, combination agents with other therapies (such as photodynamic photothermal therapy) demonstrated enhanced tumor-targeting efficiency efficacy. Finally, opportunities challenges faced by liposome nanoformulations entering clinical highlighted.

Language: Английский

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