DOCSLIB.ORG

The Impact of Transcription on Metabolism in Prostate and Breast Cancers

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Impact of Transcription on Metabolism in Prostate and Breast Cancers 25 9 Endocrine-Related N Poulose et al. From hormones to fats and 25:9 R435–R452 Cancer back REVIEW The impact of transcription on metabolism in prostate and breast cancers Ninu Poulose1, Ian G Mills1,2,* and Rebecca E Steele1,* 1Centre for Cancer Research and Cell Biology, Queen’s University of Belfast, Belfast, UK 2Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK Correspondence should be addressed to I G Mills: [email protected] *(I G Mills and R E Steele contributed equally to this work) Abstract Metabolic dysregulation is regarded as an important driver in cancer development and Key Words progression. The impact of transcriptional changes on metabolism has been intensively f androgen studied in hormone-dependent cancers, and in particular, in prostate and breast cancer. f androgen receptor These cancers have strong similarities in the function of important transcriptional f breast drivers, such as the oestrogen and androgen receptors, at the level of dietary risk and f oestrogen epidemiology, genetics and therapeutically. In this review, we will focus on the function f endocrine therapy of these nuclear hormone receptors and their downstream impact on metabolism, with a resistance particular focus on lipid metabolism. We go on to discuss how lipid metabolism remains dysregulated as the cancers progress. We conclude by discussing the opportunities that this presents for drug repurposing, imaging and the development and testing of new Endocrine-Related Cancer therapeutics and treatment combinations. (2018) 25, R435–R452 Introduction: prostate and breast cancer Sex hormones act through nuclear hormone receptors Early-stage PCa is dependent on androgens for survival and induce distinct transcriptional programmes essential and can be treated by androgen deprivation therapy; to male and female physiology. They exert their effects however, with the advancement of cancer, it becomes on target tissues such as the mammary gland, ovary and refractory to hormone treatment. This later stage of PCa the uterus in females and the testis and the prostate is known as castrate-resistant PCa (CRPC) or androgen- gland in males. Studies indicate that these hormones indifferent PCa, meaning that the cancer thrives despite a also play pivotal roles in the development of endocrine- reduction in serum androgen levels (Feldman & Feldman related cancers. The highest incidence cancers affecting 2001, Beltran et al. 2011). The prostate is also a target for hormone-dependent organs are prostate cancer (PCa) oestrogens among which oestradiol-17β is considered and breast cancer (BCa). PCa is the second most common the most potent inducer of prostatic proliferation and male malignancy in many western industrialised promotes epithelial-to-mesenchymal transition in countries and fifth leading cause of cancer death in men benign prostatic epithelial cells (Shi et al. 2017). Studies worldwide (GLOBOCAN 2012). BCa is the most frequently also suggest that oestrogen–androgen balance may be a diagnosed female malignancy and the fifth most common key determinant in the development of aggressive PCa cause of death from cancer overall (GLOBOCAN 2012). (Black et al. 2014). Likewise androgens play important http://erc.endocrinology-journals.org © 2018 Society for Endocrinology https://doi.org/10.1530/ERC-18-0048 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 06:03:19AM via free access -18-0048 Endocrine-Related N Poulose et al. From hormones to fats and 25:9 R436 Cancer back roles in the development and progression of BCa subtypes tissues bound to serum sex hormone-binding globulin such as molecular apocrine tumours (Robinson et al. and albumin, where it is converted to the more active 2011). Endogenous oestrogen levels have been linked metabolite, DHT by the enzyme 5α-reductase (Heinlein & to an increased risk of breast and endometrial cancers Chang 2004, Eacker et al. 2008). (Brown & Hankinson 2015). AR also known as NR3C4 (nuclear receptor subfamily The predominant BCa subtype is luminal tumours, 3, group C, member 4) is a ligand-dependent TF that accounting for approximately two-thirds of all diagnosed regulates the expression of genes involved in male BCa cases (Ignatiadis & Sotiriou 2013). Originating from sexual phenotype. AR gene encodes a protein of 110 KDa breast luminal epithelial cells, the majority of luminal with three major domains, the N-terminal domain, tumours are oestrogen receptor (ER) positive, and clinical the DNA-binding domain and the C-terminal ligand- studies have highlighted a strong ovarian-derived steroid binding domain (LBD). Binding of androgens to LBD hormone-driven biology, in mammary gland tumour causes dissociation of heat shock proteins, its nuclear development, particularly associated with oestradiol- translocation through binding of importin-α, subsequent 17β (Pike et al. 1993, Perou et al. 2000). ER-positive BCa dimerisation and binding to androgen response elements patients have the most favourable BCa subtype prognosis, in the promoter regions of target genes, such as prostate- generally responding well to endocrine-targeted therapies; specific antigen (PSA) and transmembrane protease serine however, endocrine therapy resistance does occur (García- 2 (Tan et al. 2015). AR is expressed mostly in the secretory Becerra et al. 2013). In recent years, an important role for epithelial cells and to some extent in the stroma, whereas the androgen receptor (AR) in breast tumourigenesis has basal cells are AR negative (Prins et al. 1991). In a fully emerged, with between 70 and 90% of tumours shown to formed prostate, the androgens continue to function to harbour AR positivity (Moinfar et al. 2003, Niemeier et al. promote the survival of secretory epithelia. Physiological 2010, Collins et al. 2011). In addition, two gene expression testosterone and DHT levels prevented apoptosis in these studies have identified an AR-positive BCa subtype; secretory epithelial cells, whereas castration resulted in a molecular apocrine BCa tumours, also characterised by loss of prostate secretory epithelial cells due to apoptosis ER negativity, they constitute 8–12% of all BCa cases in rat models, which was preceded by degeneration of (Farmer et al. 2005, Doane et al. 2006). Despite their prostatic capillaries (Heinlein & Chang 2004). Hence, ER-negative status, molecular apocrine tumours express a AR signalling remains essential to the structural and number of genes that are usually expressed in ER-positive functional integrity of prostate gland. tumours such as XBP-1, SCUBE2, SPDEF and FOXA1 ER signalling is important for a number of normal (Doane et al. 2006, Robinson et al. 2011). It is proposed cellular proliferative processes and the maintenance of that in such tumours, in the absence of ER, AR can bind to lipid and carbohydrate metabolic homeostasis, primarily ER cis-regulatory genomic elements and transcriptionally in reproduction-related tissues (Nilsson & Gustafsson activate canonical ER target genes (Robinson et al. 2011). 2011, Vrtačnik et al. 2014). In addition, the role of Consequently, patients with molecular apocrine tumours the ER in both BCa and PCa development has been display poor clinical response to ER antagonists, and extensively studied. Like testosterone, oestrogen is a it is believed that the use of anti-androgens may be of steroid hormone, derived from cholesterol; it mediates increasing therapeutic benefit (Farmer et al. 2005). its function through binding to one of two cognate ERs – alpha (ERα) and beta (ERβ). Two ERα isoforms ERα36 (Wang et al. 2005) and ER 46 (Flouriot et al. 2000) Nuclear hormone receptors – AR and ER α have additionally been identified. Although there are Nuclear hormone receptors such as the AR and ER are two subtypes, ERα is the main driver in ER-positive ligand-activated transcription factors (TFs), which induce BCa and the main subtype of focus in this review. distinct transcriptional programmes conducive to the Upon ligand activation, ERα dimerises and interacts development and differentiation of prostate and breast with transcriptional coregulators to bind to oestrogen- tissues, respectively. The growth and maintenance of responsive elements upstream of ERα target genes (May the prostate is dependent on androgens, testosterone & Westley 1988, Hayashi et al. 2003). ERα is primarily and 5α-dihydrotestosterone (DHT), acting through expressed in the mammary gland and is a ligand- their cognate receptor, AR (Heinlein & Chang 2004). inducible TF and signal transducer that has functional Testosterone is synthesised from cholesterol, primarily by roles in proliferation, differentiation and migration and the Leydig cells in the testes and transported to the target is known to transcriptionally regulate genes involved http://erc.endocrinology-journals.org © 2018 Society for Endocrinology https://doi.org/10.1530/ERC-18-0048 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 06:03:19AM via free access Endocrine-Related N Poulose et al. From hormones to fats and 25:9 R437 Cancer back in mitochondrial biogenesis, the TCA cycle and lipid Metabolic reprogramming in prostate and metabolism (Huss et al. 2004, Manavathi et al. 2013). breast cancer Consequently, the overexpression of ER-α, as observed in many Luminal A BCa tumours, leads to hormone- Understanding the unique metabolic landscape of normal dependent breast tumourigenesis (Barnes et
Load more

Recommended publications
  • Neurosteroids and Brain Sterols
    NEUROSTEROIDS AND BRAIN STEROLS Lathe, R. and Seckl, J.R. To appear in: Mason, J.I. (ed.) Genetics of Steroid Biosynthesis and Function. Modern Genetics, volume 6, Harwood Academic, Amsterdam. in press (2002). Now published as Lathe, R., and Seckl, J.R. (2002). Neurosteroids and brain sterols. In: Mason, J.I. (ed.) Genetics of Steroid Biosynthesis and Function. Modern Genetics, volume 6, Harwood Academic, Amsterdam. pp 405-472. File:-//integra/t&f/Gsb/3b2/Gsbc15.3d ± Date:-19.12.2001 ± Time:-4:23pm 15.NEUROSTEROIDSANDBRAINSTEROLS RICHARD LATHE*,y AND JONATHAN R. SECKL* *Centre for Genome Research and Molecular Medicine Centre, Centre for Neuroscience, The University of Edinburgh, King's Buildings, Edinburgh EH93JQ , UK Conventionally, steroids operate via transcription, but a subclass of brain-active steroids, dubbed neurosteroids, may govern cognitive processes via membrane-associated receptors. De novo synthesis of neurosteroids within the brain has been discussed; we suggest that these may derive primarily from the circulation. In contrast, the brain is largely self-sufficient in cholesterol. Synthesis and metabolism of cholesterol and its oxysterol derivatives appears to be crucial to brain development and function, emphasized by drugs (anti-convulsants, neuroleptics)and mutations (Smith-Lemli-Opitz, Niemann-Pick disease type C, cerebrotendinous xanthamatosis)that affect these pathways and have marked brain effects. Receptors for steroids and sterols are discussed, particularly those at cell-surface and intracellular membranes including sites of sterol metabolism and trafficking (including sigma-1, the emopamil binding protein [EBP], and the peripheral benzodiazepine receptor [PBR]). Potential overlaps between sterol and steroid signaling are discussed. In addition to regulating neuronal activity, we suggest that steroids and sterols may regulate proliferative and degenerative processes in the brain including apoptosis induction.
    [Show full text]
  • Cholesterol Metabolites 25-Hydroxycholesterol and 25-Hydroxycholesterol 3-Sulfate Are Potent Paired Regulators: from Discovery to Clinical Usage
    H OH metabolites OH Review Cholesterol Metabolites 25-Hydroxycholesterol and 25-Hydroxycholesterol 3-Sulfate Are Potent Paired Regulators: From Discovery to Clinical Usage Yaping Wang 1, Xiaobo Li 2 and Shunlin Ren 1,* 1 Department of Internal Medicine, McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23249, USA; [email protected] 2 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; [email protected] * Correspondence: [email protected]; Tel.: +1-(804)-675-5000 (ext. 4973) Abstract: Oxysterols have long been believed to be ligands of nuclear receptors such as liver × recep- tor (LXR), and they play an important role in lipid homeostasis and in the immune system, where they are involved in both transcriptional and posttranscriptional mechanisms. However, they are increas- ingly associated with a wide variety of other, sometimes surprising, cell functions. Oxysterols have also been implicated in several diseases such as metabolic syndrome. Oxysterols can be sulfated, and the sulfated oxysterols act in different directions: they decrease lipid biosynthesis, suppress inflammatory responses, and promote cell survival. Our recent reports have shown that oxysterol and oxysterol sulfates are paired epigenetic regulators, agonists, and antagonists of DNA methyl- transferases, indicating that their function of global regulation is through epigenetic modification. In this review, we explore our latest research of 25-hydroxycholesterol and 25-hydroxycholesterol 3-sulfate in a novel regulatory mechanism and evaluate the current evidence for these roles. Citation: Wang, Y.; Li, X.; Ren, S. Keywords: oxysterol sulfates; oxysterol sulfation; epigenetic regulators; 25-hydroxysterol; Cholesterol Metabolites 25-hydroxycholesterol 3-sulfate; 25-hydroxycholesterol 3,25-disulfate 25-Hydroxycholesterol and 25-Hydroxycholesterol 3-Sulfate Are Potent Paired Regulators: From Discovery to Clinical Usage.
    [Show full text]
  • Cholesterol Metabolites Exported from Human Brain
    Steroids xxx (2015) xxx–xxx Contents lists available at ScienceDirect Steroids journal homepage: www.elsevier.com/locate/steroids Cholesterol metabolites exported from human brain Luigi Iuliano a, Peter J. Crick b,1, Chiara Zerbinati a, Luigi Tritapepe c, Jonas Abdel-Khalik b, Marc Poirot d, ⇑ ⇑ Yuqin Wang b, , William J. Griffiths b, a Department of Medico-Surgical Sciences and Biotechnology, Sapienza University of Rome, corso della Repubblica 79, Latina 04100, Italy b College of Medicine, Grove Building, Swansea University, Singleton Park, Swansea SA2 8PP, UK c Department of Anesthesiology and Intensive Care, Sapienza University of Rome, vial del Policlinico 163, Rome 00161, Italy d UMR 1037 INSERM-University Toulouse III, Cancer Research Center of Toulouse, and Institut Claudius Regaud, 31052 Toulouse, France article info abstract Article history: The human brain contains approximately 25% of the body’s cholesterol. The brain is separated from the Received 16 December 2014 circulation by the blood brain barrier. While cholesterol will not passes this barrier, oxygenated forms of Received in revised form 13 January 2015 cholesterol can cross the barrier. Here by measuring the difference in the oxysterol content of blood Accepted 23 January 2015 plasma in the jugular vein and in a forearm vein by mass spectrometry (MS) we were able to determine Available online xxxx the flux of more than 20 cholesterol metabolites between brain and the circulation. We confirm that 24S- hydroxycholesterol is exported from brain at a rate of about 2–3 mg/24 h. Gas chromatography (GC)–MS Keywords: data shows that the cholesterol metabolites 5a-hydroxy-6-oxocholesterol (3b,5a-dihydroxycholestan-6- Oxysterol one), 7b-hydroxycholesterol and 7-oxocholesterol, generally considered to be formed through reactive LC–MS GC–MS oxygen species, are similarly exported from brain at rates of about 0.1, 2 and 2 mg/24 h, respectively.
    [Show full text]
  • An Examination of Oxysterol Effects on Membrane Bilayers Using Molecular Dynamics Simulations Brett Olsen Washington University in St
    Washington University in St. Louis Washington University Open Scholarship All Theses and Dissertations (ETDs) January 2010 An Examination of Oxysterol Effects on Membrane Bilayers Using Molecular Dynamics Simulations Brett Olsen Washington University in St. Louis Follow this and additional works at: https://openscholarship.wustl.edu/etd Recommended Citation Olsen, Brett, "An Examination of Oxysterol Effects on Membrane Bilayers Using Molecular Dynamics Simulations" (2010). All Theses and Dissertations (ETDs). 420. https://openscholarship.wustl.edu/etd/420 This Dissertation is brought to you for free and open access by Washington University Open Scholarship. It has been accepted for inclusion in All Theses and Dissertations (ETDs) by an authorized administrator of Washington University Open Scholarship. For more information, please contact [email protected]. Washington University in Saint Louis Division of Biology and Biological Sciences Program in Molecular and Cellular Biology Dissertation Examination Committee: Nathan Baker, Chair Douglas Covey Katherine Henzler-Wildman Garland Marshall Daniel Ory Paul Schlesinger An Examination of Oxysterol Effects on Membrane Bilayers Using Molecular Dynamics Simulations by Brett Neil Olsen A dissertation presented to the Graduate School of Arts and Sciences of Washington University in partial fulfillment of the requirements for the degree of Doctor of Philosophy August 2010 Saint Louis, Missouri Acknowledgments I would like to thank my doctoral adviser Nathan Baker, whose guidance and advice has been essential to my development as an independent researcher, and whose confidence in my abilities has often surpassed my own. Thanks to my experimental collaborators at Washington University: Paul Schlesinger, Daniel Ory, and Doug Covey, without whom this work never would have been begun.
    [Show full text]
  • Do Oxysterols Control Cholesterol Homeostasis?
    Do oxysterols control cholesterol homeostasis? Ingemar Björkhem J Clin Invest. 2002;110(6):725-730. https://doi.org/10.1172/JCI16388. Perspective Oxysterols are oxygenated derivatives of cholesterol with a very short half-life relative to cholesterol. As a consequence they are present in very low concentrations in all mammalian systems, almost invariably accompanied by 103- to 106-fold excess of cholesterol. Oxysterols are important intermediates in a number of hepatic and extrahepatic catabolic pathways, most of which generate water-soluble bile acids as final products. Based on largely indirect evidence, and in spite of their low levels in vivo, oxysterols are generally believed to be important physiological mediators of cholesterol- induced effects. Perhaps the best support for this model is the existence of nuclear receptors that bind these compounds with high affinity and the fact that oxysterols potently regulate the expression of sterol-sensitive genes in vitro. Here I consider the role of oxysterols as intermediates in different catabolic pathways, and I weigh the evidence for and against the “oxysterol hypothesis” of cholesterol homeostasis. Oxygenation in cholesterol metabolism Cholesterol synthesis requires only one oxygenation reaction, but several such steps are necessary in its degradation to bile acids and its conversion to steroid hormones. Introduction of an oxygen atom in cholesterol drastically reduces its half-life and directs the molecule to leave the body. The physical properties of oxysterols facilitate their degradation and excretion, as oxysterols are able to pass lipophilic membranes much more quickly than does cholesterol […] Find the latest version: https://jci.me/16388/pdf PERSPECTIVE Biology and biochemistry of cholesterol | Ira Tabas, Series Editor Do oxysterols control cholesterol homeostasis? Ingemar Björkhem Division of Clinical Chemistry, Karolinska Institutet, Huddinge University Hospital, Huddinge, Sweden J.
    [Show full text]
  • The Role of Autophagy in Survival Response Induced by 27- T Hydroxycholesterol in Human Promonocytic Cells
    Redox Biology 17 (2018) 400–410 Contents lists available at ScienceDirect Redox Biology journal homepage: www.elsevier.com/locate/redox Research Paper The role of autophagy in survival response induced by 27- T hydroxycholesterol in human promonocytic cells Beyza Vurusanera, Simona Gargiulob, Gabriella Testab, Paola Gambab, Gabriella Leonarduzzib, ⁎ Giuseppe Polib, Huveyda Basagaa, a Biological Sciences and Bioengineering Program, Faculty of Engineering and Natural Sciences, Sabanci University, Orhanli-Tuzla, 34956 Istanbul, Turkey b Department of Clinical and Biological Sciences, University of Torino, Torino, Italy ARTICLE INFO ABSTRACT Keywords: Autophagy has been shown to be stimulated in advanced atherosclerotic plaques by metabolic stress, in- Oxysterols flammation and oxidized lipids. The lack of published studies addressing the potential stimulation of pro-sur- 27-hydroxycholesterol vival autophagy by oxysterols, a family of cholesterol oxidation products, has prompted our study. Thus, the goal Autophagy of the current study is to elucidate the molecular mechanism of the autophagy induced by 27-hydroxycholesterol ROS (27-OH), that is one of the most abundant oxysterols in advanced atherosclerotic lesions, and to assess whether Survival signaling the pro-oxidant effect of the oxysterol is involved in the given response. Here we showed that 27-OH, in a low micromolar range, activates a pro-survival autophagic response in terms of increased LC3 II/LC3 I ratio and Beclin 1, that depends on the up-regulation of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/Akt pathways as a potential result of an intracellular reactive oxygen species increase provoked by the oxysterol in human promonocytic U937 cells. Moreover, 27-OH induced autophagy is dependent on the relation between nuclear factor erythroid 2 p45-related factor 2 (Nrf2)-dependent antioxidant response and p62.
    [Show full text]
  • Smith-Lemli-Opitz Syndrome and Inborn Errors of Cholesterol Synthesis
    BRIEF REPORT Smith-Lemli-Opitz syndrome and inborn errors of cholesterol synthesis: summary of the 2007 SLO/RSH Foundation scientific conference sponsored by the National Institutes of Health Louise S. Merkens, PhD1, Christopher Wassif, MS2, Kristy Healy, RN, CCRC1, Anuradha S. Pappu, PhD3, Andrea E. DeBarber, PhD3, Jennifer A. Penfield, MS, PA-C1, Rebecca A. Lindsay, BA4, Jean-Baptiste Roullet, PhD1, Forbes D. Porter, MD, PhD2, and Robert D. Steiner, MD1,5 Abstract: In June 2007, the Smith-Lemli-Opitz/RSH Foundation held a tive research projects that would ultimately improve our under- scientific conference hosted jointly by Dr. Robert Steiner from Oregon standing and treatment of SLOS and other inborn errors of Health & Science University and Dr. Forbes D. Porter from The Eunice cholesterol synthesis. Kennedy Shriver National Institute for Child Health and Human De- Several of the scientists also participated in the concurrent velopment, National Institutes of Health. The main goal of this meeting Smith-Lemli-Opitz/RSH Foundation family conference. These was to promote interaction between scientists with expertise in choles- family sessions occur every 2 years as a forum for education of terol homeostasis, brain cholesterol metabolism, developmental biol- families with affected children about SLOS and dealing with ogy, and oxysterol and neurosteroid biochemistry, clinicians research- children with a chronic disease. They are also an opportunity for ing and treating patients with Smith-Lemli-Opitz syndrome, the patient SLOS families to meet and network. The families were invited support organization and families. This report summarizes the presen- to ask questions and express concerns to a panel of physicians, tations and discussions at the conference, represents the conference psychologists, dietitians, and scientists currently working in the proceedings, and is intended to foster collaborative research and ulti- diagnosis and management of patients with SLOS.
    [Show full text]
  • Diverse Immunoregulatory Roles of Oxysterols— the Oxidized Cholesterol Metabolites
    H OH metabolites OH Review Diverse Immunoregulatory Roles of Oxysterols— The Oxidized Cholesterol Metabolites Chloe Choi 1,* and David K. Finlay 1,2,* 1 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse Street 152-160, Dublin 2, Ireland 2 School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse Street 152-160, Dublin 2, Ireland * Correspondence: [email protected] (C.C.); fi[email protected] (D.K.F.); Tel.: +353-1-896-3564 (D.K.F.) Received: 13 August 2020; Accepted: 24 September 2020; Published: 28 September 2020 Abstract: Intermediates of both cholesterol synthesis and cholesterol metabolism can have diverse roles in the control of cellular processes that go beyond the control of cholesterol homeostasis. For example, oxidized forms of cholesterol, called oxysterols have functions ranging from the control of gene expression, signal transduction and cell migration. This is of particular interest in the context of immunology and immunometabolism where we now know that metabolic processes are key towards shaping the nature of immune responses. Equally, aberrant metabolic processes including altered cholesterol homeostasis contribute to immune dysregulation and dysfunction in pathological situations. This review article brings together our current understanding of how oxysterols affect the control of immune responses in diverse immunological settings. Keywords: oxysterols; cholesterol; SREBP; LXR; GPR183; ROR; SERM; Ch25h; Cyp27a1; inflammation; cancer; infection; obesity; autoimmunity; endometriosis; immunometabolism 1. Introduction Cholesterol is a vital component of our cells and our bodies. It is a structural component of cellular membranes, plays a role in regulating intracellular signal transduction and is a precursor for the generation of other important molecules such as bile acids and steroid hormones.
    [Show full text]
  • Cholesterol Dyshomeostasis and Age Related Macular Degeneration Bhanu Chandar Dasari
    University of North Dakota UND Scholarly Commons Theses and Dissertations Theses, Dissertations, and Senior Projects 1-1-2012 Cholesterol Dyshomeostasis And Age Related Macular Degeneration Bhanu Chandar Dasari Follow this and additional works at: https://commons.und.edu/theses Recommended Citation Dasari, Bhanu Chandar, "Cholesterol Dyshomeostasis And Age Related Macular Degeneration" (2012). Theses and Dissertations. 1235. https://commons.und.edu/theses/1235 This Thesis is brought to you for free and open access by the Theses, Dissertations, and Senior Projects at UND Scholarly Commons. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of UND Scholarly Commons. For more information, please contact [email protected]. CHOLESTEROL DYSHOMEOSTASIS AND AGE RELATED MACULAR DEGENERATION by Bhanu Chandar Dasari Bachelor of Science, Kakatiya University, 1999 Master of Science, University of Pune, 2001 A Dissertation Submitted to the Graduate Faculty of the University of North Dakota in partial fulfillment of the requirements for the degree of Doctor of Philosophy Grand Forks, North Dakota May 2012 This dissertation, submitted by Bhanu Chandar Dasari in partial fulfillment of the requirements for the Degree of Doctor of Philosophy from the University of North Dakota, has been read by the Faculty Advisory Committee under whom the work has been done and is hereby approved. __________________________________ Othman Ghribi, Ph.D. __________________________________ Brij B. Singh, Ph.D. __________________________________ Colin K. Combs, Ph.D. __________________________________ James E. Porter, Ph.D. __________________________________ Saobo Lei, Ph.D. This dissertation is being submitted by the appointed advisory committee as having met all of the requirements of the Graduate School at the University of North Dakota and is hereby approved.
    [Show full text]
  • ER–Lysosome Contacts Enable Cholesterol Sensing by Mtorc1 and Drive Aberrant Growth Signalling in Niemann–Pick Type C
    ARTICLES https://doi.org/10.1038/s41556-019-0391-5 ER–lysosome contacts enable cholesterol sensing by mTORC1 and drive aberrant growth signalling in Niemann–Pick type C Chun-Yan Lim1,2, Oliver B. Davis1,2, Hijai R. Shin1,2, Justin Zhang1,2, Charles A. Berdan1,3, Xuntian Jiang4, Jessica L. Counihan1,3, Daniel S. Ory4, Daniel K. Nomura 1,3 and Roberto Zoncu 1,2* Cholesterol activates the master growth regulator, mTORC1 kinase, by promoting its recruitment to the surface of lysosomes by the Rag guanosine triphosphatases (GTPases). The mechanisms that regulate lysosomal cholesterol content to enable mTORC1 signalling are unknown. Here, we show that oxysterol binding protein (OSBP) and its anchors at the endoplasmic retic- ulum (ER), VAPA and VAPB, deliver cholesterol across ER–lysosome contacts to activate mTORC1. In cells lacking OSBP, but not other VAP-interacting cholesterol carriers, the recruitment of mTORC1 by the Rag GTPases is inhibited owing to impaired transport of cholesterol to lysosomes. By contrast, OSBP-mediated cholesterol trafficking drives constitutive mTORC1 activa- tion in a disease model caused by the loss of the lysosomal cholesterol transporter, Niemann–Pick C1 (NPC1). Chemical and genetic inactivation of OSBP suppresses aberrant mTORC1 signalling and restores autophagic function in cellular models of Niemann–Pick type C (NPC). Thus, ER–lysosome contacts are signalling hubs that enable cholesterol sensing by mTORC1, and targeting the sterol-transfer activity of these signalling hubs could be beneficial in patients with NPC. he exchange of contents and signals between organelles is key of cholesterol within the lysosome, compromising its functional- to the execution of cellular programs for growth and homeo- ity and triggering NPC—a fatal metabolic and neurodegenerative stasis, and failure of this communication can cause disease.
    [Show full text]
  • Effects of Oxysterols on Cell Viability, Inflammatory
    Effects of oxysterols on cell viability, inflammatory cytokines, VEGF, and reactive oxygen species production on human retinal cells: cytoprotective effects and prevention of VEGF secretion by resveratrol. B. Dugas, Soeli Charbonnier, Mauhamad Baarine, Kevin Ragot, Dominique Delmas, Franck Ménétrier, J. Lherminier, L. Malvitte, T. Khalfaoui, A. Bron, et al. To cite this version: B. Dugas, Soeli Charbonnier, Mauhamad Baarine, Kevin Ragot, Dominique Delmas, et al.. Effects of oxysterols on cell viability, inflammatory cytokines, VEGF, and reactive oxygen species production on human retinal cells: cytoprotective effects and prevention of VEGF secretion by resveratrol.. European Journal of Nutrition, Springer Verlag, 2010, 49 (7), pp.435-46. 10.1007/s00394-010-0102-2. hal- 00514897 HAL Id: hal-00514897 https://hal.archives-ouvertes.fr/hal-00514897 Submitted on 3 Sep 2010 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. 1 Effects of oxysterols on cell viability, inflammatory cytokines, VEGF and reactive oxygen species production on human retinal cells: cytoprotective effects and prevention of VEGF secretion by resveratrol B. Dugasa,b, S. Charbonniera, M. Baarinea, K. Ragota, D. Delmasa, F. Ménétrierc, J. Lherminierd, L. Malvittea,b, T. Khalfaouia, A.
    [Show full text]
  • Sterol and Oxysterol Synthases Near the Ciliary Base Activate the Hedgehog Pathway
    REPORT Sterol and oxysterol synthases near the ciliary base activate the Hedgehog pathway Sarah Findakly1,2, Vikas Daggubati1,2, Galo Garcia III3, Sydney A. LaStella1,2, Abrar Choudhury1,2, Cecilia Tran4, Amy Li4, Pakteema Tong4, Jason Q. Garcia1,2, Natasha Puri1,2,JeremyF.Reiter3,5, Libin Xu4, and David R. Raleigh1,2 Vertebrate Hedgehog signals are transduced through the primary cilium, a specialized lipid microdomain that is required for Smoothened activation. Cilia-associated sterol and oxysterol lipids bind to Smoothened to activate the Hedgehog pathway, but how ciliary lipids are regulated is incompletely understood. Here we identified DHCR7, an enzyme that produces cholesterol, activates the Hedgehog pathway, and localizes near the ciliary base. We found that Hedgehog stimulation negatively regulates DHCR7 activity and removes DHCR7 from the ciliary microenvironment, suggesting that DHCR7 primes cilia for Hedgehog pathway activation. In contrast, we found that Hedgehog stimulation positively regulates the oxysterol synthase CYP7A1, which accumulates near the ciliary base and produces oxysterols that promote Hedgehog signaling in response to pathway activation. Our results reveal that enzymes involved in lipid biosynthesis in the ciliary microenvironment promote Hedgehog signaling, shedding light on how ciliary lipids are established and regulated to transduce Hedgehog signals. Introduction The Hedgehog pathway directs gene expression programs that Cooper et al., 2003; Corcoran and Scott, 2006; Luchetti et al., are essential for development and adult tissue homeostasis, but 2016; Dwyer et al., 2007; Myers et al., 2017, 2013; Nachtergaele misactivation of the Hedgehog pathway can cause congenital et al., 2012, 2013; Nedelcu et al., 2013; Huang et al., 2018; Qi et al., disorders and cancer (Briscoe and Therond,´ 2013).
    [Show full text]