Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

Nature Metabolism, Journal Year: 2020, Volume and Issue: 2(2), P. 132 - 141

Published: Feb. 10, 2020

Language: Английский

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Free Radical Properties, Source and Targets, Antioxidant Consumption and Health

Oxygen, Journal Year: 2022, Volume and Issue: 2(2), P. 48 - 78

Published: April 12, 2022

Free radicals have acquired growing importance in the fields of biology and medicine. They are produced during many different endogenous exogenous processes. Mitochondria main source reactive oxygen species (ROS) at cell level. The overproduction free can damage macromolecules such as nucleic acids, proteins lipids. This leads to tissue various chronic degenerative diseases. Antioxidants play a crucial role body’s defense against radicals. review concerns properties radicals, their sources deleterious effects. It highlights potential dietary supplementation antioxidants discusses unsolved problems regarding antioxidant supplements prevention therapy

Language: Английский

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Cholesterol metabolism: New functions and therapeutic approaches in cancer

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2020, Volume and Issue: 1874(1), P. 188394 - 188394

Published: July 19, 2020

Language: Английский

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Lipid rafts as signaling hubs in cancer cell survival/death and invasion: implications in tumor progression and therapy

Journal of Lipid Research, Journal Year: 2020, Volume and Issue: 61(5), P. 611 - 635

Published: Jan. 27, 2020

Cholesterol/sphingolipid-rich membrane domains, known as lipid rafts or rafts, play a critical role in the compartmentalization of signaling pathways. Physical segregation proteins may modulate accessibility to regulatory effector molecules. Thus, serve sorting platforms and hubs for signal transduction proteins. Cancer cells contain higher levels intracellular cholesterol than their normal non-tumorigenic counterparts. Many processes involved cancer development (insulin-like growth factor system phosphatidylinositol 3-kinase-AKT) metastasis [cluster differentiation (CD)44] are dependent on modulated by rafts. Additional playing an important several malignant cancers (e.g., transmembrane glycoprotein mucin 1) also being detected association with suggesting major tumor progression. Conversely, scaffolds recruitment clustering Fas/CD95 death receptors downstream molecules leading cell death-promoting raft platforms. The partition aggregated has led formation so-called cluster apoptotic molecule-enriched CASMER, which leads apoptosis amplification can be pharmacologically modulated. These viewed linchpin from signals launched. In this review, we discuss involvement cells, including survival, death, metastasis, consider potential modulation promising target therapy. disintegrin metalloproteinase 10 domain death-inducing complex receptor 4 5 extracellular matrix epidermal estrogen Fas-associated protein glycosylphosphatidylinositol hyaluronic acid heat shock 90 insulin-like type 1 insulin substrate c-Jun N-terminal kinase mantle lymphoma mammalian rapamycin phosphatidylinositol-dependent pleckstrin homology 3-kinase 3,4,5-trisphosphate phosphatase tensin homolog TNF superfamily TNF-related apoptosis-inducing ligand Lipids components essential maintenance integrity numerous biological functions, division, they act energy sources tissues. Altered metabolism is newly recognized feature malignancy. For example, increased uptake, storage, occur variety contribute (1Swinnen J.V. Brusselmans K. Verhoeven G. Increased lipogenesis cells: new players, novel targets.Curr. Opin. Clin. Nutr. Metab. Care. 2006; 9: 358-365Crossref PubMed Scopus (422) Google Scholar, 2Cheng C. Geng F. Cheng X. Guo D. Lipid reprogramming its targets cancer.Cancer Commun. (Lond.). 2018; 38: 27Crossref (90) Scholar). Cholesterol component membranes, comprising about 30% bilayer, it plays crucial function viability. building block plasma (Fig. 1), pivotal roles maintaining structural regulating permeability fluidity membranes well initiation adhesion (ECM) (3Chapman Phase transitions characteristics lipids membranes.Q. Rev. Biophys. 1975; 8: 185-235Crossref 4Jaipuria Ukmar-Godec T. Zweckstetter M. Challenges approaches understand cholesterol-binding impact function: NMR view.Cell. Mol. Life Sci. 75: 2137-2151Crossref (13) addition central biogenesis cellular organization, serves precursor different that physiology cancer, steroid hormones, oxysterols, vitamin D, estrogen-related α (5Chimento A. Casaburi I. Avena P. Trotta De Luca Rago V. Pezzi Sirianni R. metabolites growth: therapeutic statins treatment.Front. Endocrinol. (Lausanne). 2019; 807Crossref (12) Scholar), even opposite actions progression 1). 27-hydroxycholesterol, most abundant oxysterol plasma, oxygenated derivatives formed enzymatic radical oxidation, affect distinct tumors way (6Kloudova Guengerich F.P. Soucek oxysterols human cancer.Trends 2017; 28: 485-496Abstract Full Text PDF (65) Oxysterols have been reported promote proliferation (7Wu Q. Ishikawa Tang H. McDonald J.G. Yuhanna I.S. Thompson B. Girard L. Mineo Brekken R.A. et al.27-Hydroxycholesterol promotes cell-autonomous, ER-positive breast growth.Cell Reports. 2013; 5: 637-645Abstract (0) recruit pro-tumor neutrophils (8Raccosta Fontana Maggioni Lanterna Villablanca E.J. Paniccia Musumeci Chiricozzi E. Trincavelli M.L. Daniele S. al.The oxysterol-CXCR2 axis key tumor-promoting neutrophils.J. Exp. Med. 210: 1711-1728Crossref (102) 9Soncini Corna Moresco Coltella N. Restuccia U. Raccosta Lin C.Y. Invernizzi Crocchiolo al.24-Hydroxycholesterol participates pancreatic neuroendocrine development.Proc. Natl. Acad. USA. 2016; 113: E6219-E6227Crossref seem (10Mollinedo Neutrophil degranulation, plasticity, metastasis.Trends Immunol. 40: 228-242Abstract (52) facilitate 11Baek A.E. Yu Y.A. He Wardell S.E. Chang Kwon Pillai R.V. McDowell H.B. J.W. Dubois L.G. metabolite 27 hydroxycholesterol facilitates through immune cells.Nat. 864Crossref (107) However, suppress acting ligands LXRs (12Vedin L.L. Lewandowski S.A. Parini Gustafsson J.A. Steffensen K.R. LXR inhibits cells.Carcinogenesis. 2009; 30: 575-579Crossref (125) 13Vedin LXRalpha LXRbeta colon.Mol. Carcinog. 52: 835-844Crossref Another steroid, shown exert chemoprotective action tumors, such colorectal prostate (14Theodoratou Farrington S.M. Tenesa McNeill Cetnarskyj Barnetson Porteous M.E. Dunlop M.G. Campbell Modification inverse between dietary D intake risk FokI variant supports Vitamin mediated VDR binding.Int. J. Cancer. 2008; 123: 2170-2179Crossref (47) 15Li Stampfer M.J. Hollis J.B. Mucci L.A. Gaziano J.M. Hunter Giovannucci E.L. Ma A prospective study metabolites, polymorphisms, cancer.PLoS 2007; 4: e103Crossref (226) number other functions. It estrogens, high associated (16Yager J.D. Davidson N.E. Estrogen carcinogenesis cancer.N. Engl. 354: 270-282Crossref (1259) As stated above, functional endogenous agonist α, fatty metabolism, skeletal homeostasis mitochondrial (17Wei W. Schwaid A.G. Wang Chen Chu Saghatelian Wan Y. Ligand activation ERRalpha mediates statin bisphosphonate effects.Cell 23: 479-491Abstract 18Casaburi Chimento Nocito Sculco agonist: perspective 525Crossref (7) above processes, regulator responsible close packing acyl chains phospholipids, promoting phase separation, stabilizing cholesterol- sphingolipid-rich microdomains (19Simons Ikonen Functional membranes.Nature. 1997; 387: 569-572Crossref (7622) 20Maxfield F.R. van Meer Cholesterol, cells.Curr. Cell Biol. 2010; 22: 422-429Crossref (191) constitute centers organization trafficking (21Simons Toomre transduction.Nat. 2000; 1: 31-39Crossref 22Ikonen Roles transport.Curr. 2001; 13: 470-477Crossref (531) 23Mollinedo Gajate regulation cancer.Adv. Regul. 2015; 57: 130-146Crossref (162) On hand, androgens, (24Pelton Freeman M.R. Solomon cancer.Curr. Pharmacol. 2012; 12: 751-759Crossref (138) preclinical studies mouse models showed enhanced mice fed cholesterol-enriched diet (25Llaverias Danilo Witkiewicz A.K. Daumer Lisanti M.P. Frank P.G. Western-type accelerates autochthonous model cancer.Am. Pathol. 177: 3180-3191Abstract (73) varying ways, generation required proliferating wide array diverse pro- anti-tumor functions Importantly, fate. either obtained synthesized de novo cell. content narrowly balanced metabolic intrinsic distribution organism, homeostatic mechanism seems disrupted cells. early 1900s, reports (26Jowett phosphatide contents tissues.Biochem. 1931; 25: 1991-1998Crossref 27Yasuda Bloor W.R. tumors.J. Invest. 1932; 11: 677-682Crossref 28Roffo A.H. Heliotropism relation skin 1933; 17: 42-57Crossref 29Knudson Sturges Bryan skin, blood, tissue rats irradiated ultraviolet light.J. Chem. 1939; 128: 721-727Abstract 30Mulas M.F. Abete Pulisci Pani Massidda Dessi Mandas esters regulators lymphocytic leukaemia cells.Cell Prolif. 2011; 44: 360-371Crossref Scholar) were surrounding tissues compared derived. now generally accepted tend types (31Krycer J.R. 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Hughes Murray L.J. after diagnosis survival: population-based Oncol. 32: 3177-3183Crossref 51Epstein M.M. Divine Chao Wells K.E. Feigelson H.S. Scholes Roblin Ulcickas Yood Engel L.S. Taylor al.Statin myeloma: analysis research network.Int. 141: 480-487Crossref (9) 52Van Rompay M.I. Nickel J.C. Ranganathan Kantoff P.W. McKinlay Prostate among using non-statin lipid-lowering medications.Eur. 112: 118-126Abstract 53Akinwunmi Vitonis A.F. Titus Terry K.L. Cramer D.W. therapy ovarian New England Case Control (NEC) study.Int. 144: 991-1000Crossref suggests could appearance cancer. contrast, did find (54Shepherd Blauw G.J. Murphy M.B. Bollen Buckley Cobbe Ford Gaw Hyland Jukema al.Pravastatin elderly individuals at vascular (PROSPER): randomised controlled trial.Lancet. 2002; 360: 1623-1630Abstract (2806) 55Beckwitt C.H. Brufsky Oltvai Z.N. reduce recurrence mortality.Breast 20: 144Crossref (42) Overall, mixed largely both question particular used (56Clendening Penn L.Z. Targeting statins.Oncogene. 31: 4967-4978Crossref (146) Statins inhibit rate-limiting enzyme converts HMG-CoA into mevalonate, turn synthesis products, cholesterol, ubiquinone, dolichol, isoprenoids geranylgeranyl pyrophosphate farnesyl bind small GTP-binding proteins, RAS RHO, facilitating translocation cytosol (57Gbelcová Lenicek Zelenka Knejzlik Dvorakova Zadinova Pouckova Kudla Balaz Ruml al.Differences antitumor effects various cancer.Int. 122: 1214-1221Crossref (81) 58Gbelcová Rimpelova Sachova Kolar Strnad Repiska D'Acunto W.C. Vitek Isoprenoids prenylation cells.Lipids Health 16: 250Crossref (8) inhibition mevalonate pathway provokes pleiotropic effects, although sensitivity lines varies, ambiguous clinical trials (59Göbel Breining Rauner Hofbauer L.C. Rachner T.D. Induction 3-hydroxy-3-methylglutaryl-CoA reductase resistance Death 10: 91Crossref (24) Unlike epidemiologic abnormal risk, compelling laboratory studies. latter indicate capable proliferation, migration, pathways mammary cancers. vivo indicated regulate (45Danilo Neoplastic diseases particularly (60Tosi Tugnoli Cholesteryl malignancy.Clin. Chim. 359: 27-45Crossref (72) Because follows rapidly require Alterations increase cholesteryl suggested to: biosynthesis HMG-CoA-reductase synthesis; 2) uptake exogenous overexpression LDL-receptor, LDLs bloodstream transporters cholesterol; 3) esterification acyltransferase ester storage droplets (61Petan Jarc Jusovic guardians fat stressful world.Molecules. E1941Crossref (78) Scholar); 4) lower efflux dynamic nature together uneven specialized where selectively included excluded. structurally heterogeneous discrete domains unique physical properties, coexistence liquid-disordered liquid-ordered phases same bilayer. 1997, Simons hypothesis, defined sphingolipids lipid-ordered platforms, move within fluid subdomains enriched glycosphingolipids phospholipids acylated saturated acids. assemblies harbor molecules, so float freely bilayer sizes depending composition, clustered form larger stabilized consensus definition emerged 2006 Keystone Symposium Rafts Function held Steamboat Springs, CO, follows: "membrane (10–200 nm), heterogeneous, highly dynamic, sterol- sphingolipid-enriched compartmentalize processes. Small sometimes protein-protein protein-lipid interactions" (Ref. 62Pike defined: report Function.J. 47: 1597-1598Abstract (963) Scholar; p. 1597). tight interactions sterols lead characteristic solubilization

Language: Английский

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Terpenoids and Polyphenols as Natural Antioxidant Agents in Food Preservation

Antioxidants, Journal Year: 2021, Volume and Issue: 10(8), P. 1264 - 1264

Published: Aug. 8, 2021

Synthetic antioxidant food additives, such as BHA, BHT and TBHQ, are going through a difficult time, since these products generate negative perception in consumers. This has generated an increased pressure on manufacturers to search for safer natural alternatives like phytochemicals (such polyphenols, including flavonoids, essential oils rich terpenoids, carotenoids). These plant bioactive compounds have activities widely proven vitro tests diverse matrices (meat, fish, oil vegetables). As tons of wasted every year due aesthetic reasons (lipid oxidation) premature damage caused by inappropriate packaging, there is urgent need antioxidants capable replacing the synthetic ones meet consumer demands. review summarizes industrially interesting bioactivities associated with terpenoids polyphenols respect prevention lipid oxidation high fat containing foods, meat (rich saturated fat), fish polyunsaturated vegetable products, while avoiding generation rancid flavors visual deterioration color changes oxidized lipids). Terpenoids (like monoterpenes carotenoids) quercetin other flavonoids) important broad range effects. distributed fruits vegetables, agricultural waste, remarkably useful preservation, they show bioactivity antioxidants, able scavenge reactive oxygen nitrogen species, superoxide, hydroxyl or peroxyl radicals contributing processes matrices.

Language: Английский

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Obesity, Type 2 Diabetes, and Cancer Risk

Frontiers in Oncology, Journal Year: 2021, Volume and Issue: 10

Published: Feb. 2, 2021

Obesity and type 2 diabetes have both been associated with increased cancer risk are becoming increasingly prevalent. Metabolic abnormalities such as insulin resistance dyslipidemia obesity implicated in the obesity-cancer relationship. Multiple mechanisms proposed to link progression, including an increase insulin/IGF-1 signaling, lipid glucose uptake metabolism, alterations profile of cytokines, chemokines, adipokines, well changes adipose tissue directly adjacent sites. This review aims summarize provide update on epidemiological mechanistic evidence linking cancer, focusing roles insulin, lipids, tissue.

Language: Английский

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7-Ketocholesterol in disease and aging

Redox Biology, Journal Year: 2019, Volume and Issue: 29, P. 101380 - 101380

Published: Nov. 14, 2019

7-Ketocholesterol (7KC) is a toxic oxysterol that associated with many diseases and disabilities of aging, as well several orphan diseases. 7KC the most common product reaction between cholesterol oxygen radicals concentrated found in blood arterial plaques coronary artery disease patients various other tissues cell types. Unlike cholesterol, consistently shows cytotoxicity to cells its physiological function humans or complex organisms unknown. Oxysterols, particularly 7KC, have also been shown diffuse through membranes where they affect receptor enzymatic function. Here, we will explore known proposed mechanisms pathologies are speculate about future diagnostic therapeutic target medicine.

Language: Английский

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Mechanisms and Barriers in Nanomedicine: Progress in the Field and Future Directions

ACS Nano, Journal Year: 2024, Volume and Issue: 18(22), P. 13983 - 13999

Published: May 20, 2024

In recent years, steady progress has been made in synthesizing and characterizing engineered nanoparticles, resulting several approved drugs multiple promising candidates clinical trials. Regulatory agencies such as the Food Drug Administration European Medicines Agency released important guidance documents facilitating nanoparticle-based drug product development, particularly context of liposomes lipid-based carriers. Even with achieved, it is clear that many barriers must still be overcome to accelerate translation into clinic. At conference workshop "Mechanisms Barriers Nanomedicine" May 2023 Colorado, U.S.A., leading experts discussed formulation, physiological, immunological, regulatory, clinical, educational barriers. This position paper invites open, unrestricted, nonproprietary discussion among senior faculty, young investigators, students trigger ideas concepts move field forward.

Language: Английский

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Oxidative Stress and Reprogramming of Lipid Metabolism in Cancers

Antioxidants, Journal Year: 2025, Volume and Issue: 14(2), P. 201 - 201

Published: Feb. 10, 2025

Oxidative stress is a common event involved in cancer pathophysiology, frequently accompanied by unique lipid metabolic reprogramming phenomena. caused mainly an imbalance between the production of reactive oxygen species (ROS) and antioxidant system cells. Emerging evidence has reported that oxidative regulates expression activity metabolism-related enzymes, leading to alteration cellular metabolism; this involves significant increase fatty acid synthesis shift way which lipids are taken up utilized. The dysregulation metabolism provides abundant intermediates synthesize biological macromolecules for rapid proliferation cells; moreover, it contributes maintenance intracellular redox homeostasis producing variety reducing agents. Moreover, derivatives metabolites play critical roles signal transduction within cells tumor microenvironment evades immune destruction facilitates invasion metastasis. These findings suggest close relationship during malignant progression cancers. This review focuses on crosstalk reprogramming, in-depth insight into modulation ROS cancers discusses potential strategies targeting therapy.

Language: Английский

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Lipid Oxidation Derived Aldehydes and Oxysterols Between Health and Disease

European Journal of Lipid Science and Technology, Journal Year: 2018, Volume and Issue: 121(1)

Published: March 24, 2018

Non‐enzymatic and enzymatic oxidation of lipids has long been a primary issue in human pathophysiology, with special emphasis on diet‐ nutrition‐related aspects. While there is no doubt that the n‐3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid, docosahexaenoic exert anti‐inflammatory, inflammation resolving, immunomodulatory effects different model systems, their non‐enzymatic during food storage cooking, as well gastrointestinal digestion, can give rise to excessive amounts quite reactive aldehydic end‐products, particular 4‐hydroxyhexenal. However, n‐6 PUFAs is, principle, far more harmful, not least because one its main 4‐hydroxynonenal, shown be associated progression number diseases. Several cholesterol products, known oxysterols, are also nutritional importance; these generated body through both reactions, but may present diet due autoxidation cholesterol‐containing foods. Their potential contribution pathogenesis diseases which hypercholesterolemia risk factor, such atheroclerosis, Alzheimer's disease, some forms cancers, unanimously recognized. Practical Applications : This review highlights importance certain lipid namely 4‐hydroxyalkenals modulation processes fundamental health disease. The observations facts reviewed here underline need carefully consider pros cons dietary intake metabolic fate PUFA, cholesterol, when producing, storing, processing lipid‐containing food. Lipid common process occurs reactions . It responsible for formation several compounds, including acid (PUFA)‐derived oxysterols. Depending concentrations, molecules possess physiopathological properties involved cell viability function. At high those resulting from intense oxidative stress or intake, they onset many A correct regimen, improved storage, suitable antioxidant supplementation, should implemented counteract promotion disease development by excess oxidized lipids. (HHE, 4‐hydroxyhexenal; HNE, 4‐hydroxynonenal; ROS, oxygen species).

Language: Английский

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