DOCSLIB.ORG

Progranulin As a Biomarker and Potential Therapeutic Agent

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Progranulin As a Biomarker and Potential Therapeutic Agent Drug Discovery Today Volume 22, Number 10 October 2017 REVIEWS POST SCREEN Progranulin as a biomarker and potential therapeutic agent Reviews 1 2 1 1 Vanessa Abella , Jesús Pino , Morena Scotece , Javier Conde , 3 4 5 Francisca Lago , Miguel Angel Gonzalez-Gay , Antonio Mera , 6 7,8 1 Rodolfo Gómez , Ali Mobasheri and Oreste Gualillo 1 SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), The NEIRID Lab (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Research Laboratory 9, Santiago University Clinical Hospital, Santiago de Compostela, Spain 2 SERGAS (Servizo Galego de Saude), Division of Orthopaedic Surgery and Traumatology, Santiago University Clinical Hospital, Santiago de Compostela, Spain 3 SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), CIBERCV (Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares), Molecular and Cellular Cardiology, Research Laboratory 7, Santiago University Clinical Hospital, Building C, Travesía da Choupana S/N, Santiago de Compostela 15706, Spain 4 Epidemiology, Genetics and Atherosclerosis Research Group on Systemic Inflammatory Diseases, Universidad de Cantabria and IDIVAL, Santander, Spain 5 SERGAS (Servizo Galego de Saude), Division of Rheumatology, Santiago University Clinical Hospital, Santiago de Compostela, Spain 6 SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), The NEIRID Group, Musculoskeletal Pathology Unit, Santiago University Clinical Hospital, Santiago de Compostela, Spain 7 Department of Veterinary Pre-Clinical Sciences, School of Veterinary Medicine, University of Surrey, Guildford, and Faculty of Health and Medical Sciences, Duke of Kent Building, University of Surrey, Guildford, Surrey GU2 7XH, UK 8 Arthritis Research UK Centre for Sport, Exercise and Osteoarthritis, Queen’s Medical Centre, Nottingham NG7 2UH, UK Progranulin is a cysteine-rich secreted protein with diverse pleiotropic actions and participates in several processes, such as inflammation or tumorigenesis. Progranulin was first identified as a growth factor and, recently, it was characterised as an adipokine implicated in obesity, insulin resistance and rheumatic disease. At a central level, progranulin acts as a neurotropic and neuroprotective factor and protects from neural degeneration. In this review, we summarise the most recent research advances concerning the potential role of progranulin as a therapeutic target and biomarker in cancer, neurodegenerative and inflammatory diseases. Introduction Since the discovery of this glycoprotein, the multifunctional Progranulin (PGRN) was first identified as an acrosomal glycopro- properties of PGRN have been unravelled. It is implicated in tein in 1990, namely acrogranin, synthesised during spermatogen- multiple biological and pathological processes, such as cell esis [1]. PGRN is also known as granulin-epithelin precursor (GEP) growth, tumorigenesis [12], embryogenesis [13], wound healing [2], proepithelin [3], GP88 [4] and PC-cell-derived growth factor [14], inflammation, immunity, infection [15], insulin resistance (PCDGF) [5]. Owing to its pleiotropic nature, PGRN is secreted by a [10] or diabetes [16]; and lack of it is related to neurodegeneration broad range of tissues and it is expressed by a wide variety of cell [17]. PGRN overexpression was associated to the onset of different types, including epithelial cells, neurons, haematopoietic cells, types of cancer [18–20] and PGRN downregulation was related to skeletal muscle cells [6], macrophages [7], chondrocytes [8,9], inflammatory diseases, like osteoarthritis (OA) [21] or rheumatoid adipocytes [10] and endothelial cells [11]. arthritis (RA) [22]. Otherwise, null mutations within the gene that encodes PGRN cause frontotemporal lobar degeneration (FTLD) [23,24]. In the past few years, different studies have shed light on Corresponding author: Gualillo, O. ([email protected]) how PGRN performs its actions. In fact, the role of PGRN in 1359-6446/ã 2017 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2017.06.006 www.drugdiscoverytoday.com 1557 REVIEWS Drug Discovery Today Volume 22, Number 10 October 2017 inflammation has been studied in detail, with anti-inflammatory N-terminal signal peptide of 17 amino acids and seven and a half properties through interaction with tumour necrosis factor recep- granulin domains [5]. These granulins are named, from the N tor (TNFR) [25]. Despite its anti-inflammatory role, it is possible terminus to the C terminus, granulins p (paragranulin domain), G, that PGRN has multiple roles in inflammation. In 2012, PGRN was F, B, A, C, D and E. Granulin domains are composed of tandem described as a key adipokine mediating high-fat diet-induced repeats of a 12-cysteine motif [26]. The molecular structure of insulin-resistance by inducing upregulation of interleukin (IL)-6 individual granulin domains consists of six parallel stacked beta- expression in adipose tissue [10]. Thus, the pro- or anti-inflamma- hairpins held together by six disulfide bonds [30]. After secretion, tory function of PGRN might depend on the target tissue. In brief, proteolytic cleavage of full-length protein can take place at linker Reviews PGRN can act either as a growth factor, an anti-inflammatory regions between the granulin domains. Serine and threonine agent or an adipokine. As outlined above, PGRN is involved in proteases, such us matrix metalloproteinase (MMP)-9 [31], POST SCREEN multiple processes with diverse actions. Thus, the aim of the MMP-12 [32], MMP-14 [33], a disintegrin and metalloproteinase present review is to present the potential of PGRN as a therapeutic with thrombospondin type I motif 7 (ADAMTS-7) [34], neutrophil- target in cancer, neurodegenerative and inflammatory diseases. secreted elastase and proteinase 3 [35], can release individual granulin peptides of 6 kDa (Fig. 1). Incubation of full-length PGRN PGRN biology: structure and receptors with these proteases does not always result in the release of Human PGRN is encoded by the GRN gene, located on chromo- individual 6 kDa fragments as would be expected if the precursor some 17q21.32, which contains 12 protein-coding exons that protein was completely processed to granulin domains. At least result in three isoforms [26]. It is a protein consisting of 593 amino five intermediate products larger than 15 kDa seem to be present acids and a molecular weight of 68.5 kDa [27,28]. Owing to its after digestion with all of these proteases [17,36]. Moreover, secre- highly glycosylated character, it commonly migrates around tory leukocyte protease inhibitor (SLPI) binds directly to PGRN, 88 kDa on a western blot. The mouse ortholog Grn is located on blocking the proteolysis by elastase. Similarly, high-density lipo- chromosome 11 and encodes a 589 amino acid protein, with 79% protein (HDL) apolipoprotein AI can form a complex with PGRN homology to the human PGRN protein [28]. suppressing granulin conversion [7]. PGRN has emerged as the prototypic member of a family of Full-length PGRN and granulins are biologically active, al- structurally unique proteins, evolutionarily conserved, related though whether their effects are opposite or overlapping has to growth factors [29]. Full-length PGRN consists of a secretory not yet been clearly elucidated. For instance, PGRN plays an active P G F B A C D E Progranulin MMP-9, MMP-14, ADAMTS-7, NE, PR3 E D C A F P B P G A D F B F B E A B G C D D G P E E G A C C P F Granulins EphA2 Inflammation TNFR1/ Sortilin TNFR2 ? ? Signalling blockade Cancer Anti-inflammation FTLD Drug Discovery Today FIGURE 1 Schematic representation of progranulin (PGRN) and its receptors. Each circle represents granulin domains. PGRN can be subject to proteolytic cleavage by matrix metalloproteinase (MMP)-9, MMP-14, ADAMTS-7 (a disintegrin and metalloproteinase with thrombospondin type I motif 7), neutrophil-secreted elastase (NE) and proteinase (PR)3. Granulin individual peptides involve inflammatory effects. By contrast, full-length PGRN has an anti-inflammatory role by tumour necrosis factor receptor (TNFR) binding. Interactions between PGRN and sortilin have been implicated in frontotemporal lobar degeneration (FTLD) onset. Also, tumorigenic actions of PGRN are explained by TNFR2 or EphA2 binding. 1558 www.drugdiscoverytoday.com Drug Discovery Today Volume 22, Number 10 October 2017 REVIEWS part in resolution of inflammation, whereas granulins seem to be Rheumatoid arthritis proinflammatory. Granulin B, but not PGRN, stimulates interleu- The development of atsttrin was made in the field of inflammatory kin (IL)-8 expression in epithelial cells [36]. However, granulin E arthritis, so its effects on the pathophysiology of RA have been was reported to support neuronal cell survival similarly to PGRN extensively studied and reviewed [22,25,47,49,51,52]. In brief, [37]. atsttrin administration results in reduced disease severity in colla- It is not yet clear whether there is a unique receptor for PGRN, gen-antibody-induced arthritis (CAIA) and in the collagen-in- given the wide range of effects mediated either by PGRN or duced arthritis (CIA) mouse model. Notably, atsttrin shows granulins in different cell types. The observation that PGRN is more-potent anti-inflammatory activity than PGRN, possibly as a secreted protein that is internalised through an endocytic a result of the absence of a complete granulin domain with mechanism suggests the existence
Load more

Recommended publications
  • GRN (Human) Recombinant Protein (Q01)
    GRN (Human) Recombinant Protein and PC cell-derived growth factor. Cleavage of the (Q01) signal peptide produces mature granulin which can be further cleaved into a variety of active, 6 kDa peptides. Catalog Number: H00002896-Q01 These smaller cleavage products are named granulin A, granulin B, granulin C, etc. Epithelins 1 and 2 are Regulation Status: For research use only (RUO) synonymous with granulins A and B, respectively. Both the peptides and intact granulin protein regulate cell Product Description: Human GRN partial ORF ( growth. However, different members of the granulin NP_002078, 494 a.a. - 593 a.a.) recombinant protein protein family may act as inhibitors, stimulators, or have with GST-tag at N-terminal. dual actions on cell growth. Granulin family members are important in normal development, wound healing, and Sequence: tumorigenesis. [provided by RefSeq] SCEKEVVSAQPATFLARSPHVAVKDVECGEGHFCHD NQTCCRDNRQGWACCPYRQGVCCADRRHCCPAGF References: RCAARGTKCLRREAPRWDAPLRDPALRQLL 1. Progranulin Does Not Bind Tumor Necrosis Factor (TNF) Receptors and Is Not a Direct Regulator of Host: Wheat Germ (in vitro) TNF-Dependent Signaling or Bioactivity in Immune or Neuronal Cells. Chen X, Chang J, Deng Q, Xu J, Theoretical MW (kDa): 36.74 Nguyen TA, Martens LH, Cenik B, Taylor G, Hudson KF, Chung J, Yu K, Yu P, Herz J, Farese RV Jr, Kukar T, Applications: AP, Array, ELISA, WB-Re Tansey MG. J Neurosci. 2013 May 22;33(21):9202-13 (See our web site product page for detailed applications 2. The neurotrophic properties of progranulin depend on information) the granulin E domain but do not require sortilin binding. Protocols: See our web site at De Muynck L, Herdewyn S, Beel S, Scheveneels W, Van http://www.abnova.com/support/protocols.asp or product Den Bosch L, Robberecht W, Van Damme P Neurobiol page for detailed protocols Aging.
    [Show full text]
  • Processing of Progranulin Into Granulins Involves Multiple Lysosomal Proteases and Is Affected in Frontotemporal Lobar Degeneration
    Processing of progranulin into granulins involves multiple lysosomal proteases and is affected in frontotemporal lobar degeneration Swetha Mohan University of California San Francisco Paul J. Sampognaro University of California San Francisco Andrea R. Argouarch University of California San Francisco Jason C. Maynard University of California San Francisco Anand Patwardhan University of California San Francisco Emma C. Courtney University of California San Francisco Amanda Mason University of California San Francisco Kathy H. Li University of California San Francisco William W. Seeley University of California San Francisco Bruce L. Miller University of California San Francisco Alma Burlingame University of California San Francisco Mathew P. Jacobson University of California San Francisco Aimee Kao ( [email protected] ) University of California San Francisco https://orcid.org/0000-0002-7686-7968 Research article Keywords: Progranulin, granulin, frontotemporal lobar degeneration, lysosome, protease, pH, asparagine endopeptidase Page 1/31 Posted Date: July 29th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-44128/v2 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Version of Record: A version of this preprint was published at Molecular Neurodegeneration on August 3rd, 2021. See the published version at https://doi.org/10.1186/s13024-021-00472-1. Page 2/31 Abstract Background - Progranulin loss-of-function mutations are linked to frontotemporal lobar degeneration with TDP-43 positive inclusions (FTLD-TDP-Pgrn). Progranulin (PGRN) is an intracellular and secreted pro- protein that is proteolytically cleaved into individual granulin peptides, which are increasingly thought to contribute to FTLD-TDP-Pgrn disease pathophysiology. Intracellular PGRN is processed into granulins in the endo-lysosomal compartments.
    [Show full text]
  • Granulin: an Invasive and Survival-Determining Marker in Colorectal Cancer Patients
    International Journal of Molecular Sciences Article Granulin: An Invasive and Survival-Determining Marker in Colorectal Cancer Patients Fee Klupp 1,*, Christoph Kahlert 2, Clemens Franz 1, Niels Halama 3, Nikolai Schleussner 1, Naita M. Wirsik 4, Arne Warth 5, Thomas Schmidt 1,4 and Alexis B. Ulrich 1,6 1 Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany; [email protected] (C.F.); [email protected] (N.S.); [email protected] (T.S.); [email protected] (A.B.U.) 2 Department of Visceral, Thoracic and Vascular Surgery, University of Dresden, Fetscherstr. 74, 01307 Dresden, Germany; [email protected] 3 National Center for Tumor Diseases, Medical Oncology and Internal Medicine VI, Tissue Imaging and Analysis Center, Bioquant, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany; [email protected] 4 Department of General, Visceral und Tumor Surgery, University Hospital Cologne, Kerpener Straße 62, 50937 Cologne, Germany; [email protected] 5 Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany; [email protected] 6 Department of General and Visceral Surgery, Lukas Hospital Neuss, Preußenstr. 84, 41464 Neuss, Germany * Correspondence: [email protected]; Tel.: +49-6221-566-110; Fax: +49-6221-565-506 Abstract: Background: Granulin is a secreted, glycosylated peptide—originated by cleavage from a precursor protein—which is involved in cell growth, tumor invasion and angiogenesis. However, Citation: Klupp, F.; Kahlert, C.; the specific prognostic impact of granulin in human colorectal cancer has only been studied to a Franz, C.; Halama, N.; Schleussner, limited extent.
    [Show full text]
  • Isolation and Sequence of the Granulin Precursor Cdna from Human Bone
    Proc. Nat!. Acad. Sci. USA Vol. 89, pp. 1715-1719, March 1992 Biochemistry Isolation and sequence of the granulin precursor cDNA from human bone marrow reveals tandem cysteine-rich granulin domains (epithelin/growth factors/kidney/i ion) VIJAY BHANDARI, ROGER G. E. PALFREE, AND ANDREW BATEMAN* Endocrine Laboratory, Royal Victoria Hospital, Department of Medicine, McGill University, Montreal, PQ, H3A lAl, Canada Communicated by Seymour Lieberman, November 15, 1991 (receivedfor review September 17, 1991) ABSTRACT Granulins are candidate growth factors re- mal growth factor (EGF) (14). Some ofthese peptides may be cently discovered in human and rat inflammatory leukocytes involved in initiating or sustaining an inflammatory response and bone marrow. Two granulin homologs, epithelin 1 and 2, (15, 16), in tissue remodeling at the site of a wound by occur in the rat kidney. Epithelin 1, which is probably identical regulating matrix formation (17, 18), and in the recruitment of to rat leukocyte granulin, exhibits proliferative and antipro- neighboring fibroblasts by chemotaxis (19). The similarity liferative effects on epithelial cells in vitro. Here we show by between the molecular biology of wound repair and tumor cDNA analysis that the prepropeptide for the human granulins development has been discussed (20), and it is likely that is a 593-residue glycoprotein, containing seven tandem repeats many of the same regulatory polypeptides are involved in of the 12-cysteine granulin domain. By Northern blot analysis, both processes. gene expression was seen in myelogenous leukemic cell lines of The association of human and rat granulins with inflam- promonocytic, promyelocytic, and proerythroid lineage, in matory leukocytes (7) and the mitogenic properties of epi- fibroblasts and was seen very strongly in epithelial cell lines.
    [Show full text]
  • ©Ferrata Storti Foundation
    Original Articles T-cell/histiocyte-rich large B-cell lymphoma shows transcriptional features suggestive of a tolerogenic host immune response Peter Van Loo,1,2,3 Thomas Tousseyn,4 Vera Vanhentenrijk,4 Daan Dierickx,5 Agnieszka Malecka,6 Isabelle Vanden Bempt,4 Gregor Verhoef,5 Jan Delabie,6 Peter Marynen,1,2 Patrick Matthys,7 and Chris De Wolf-Peeters4 1Department of Molecular and Developmental Genetics, VIB, Leuven, Belgium; 2Department of Human Genetics, K.U.Leuven, Leuven, Belgium; 3Bioinformatics Group, Department of Electrical Engineering, K.U.Leuven, Leuven, Belgium; 4Department of Pathology, University Hospitals K.U.Leuven, Leuven, Belgium; 5Department of Hematology, University Hospitals K.U.Leuven, Leuven, Belgium; 6Department of Pathology, The Norwegian Radium Hospital, University of Oslo, Oslo, Norway, and 7Department of Microbiology and Immunology, Rega Institute for Medical Research, K.U.Leuven, Leuven, Belgium Citation: Van Loo P, Tousseyn T, Vanhentenrijk V, Dierickx D, Malecka A, Vanden Bempt I, Verhoef G, Delabie J, Marynen P, Matthys P, and De Wolf-Peeters C. T-cell/histiocyte-rich large B-cell lymphoma shows transcriptional features suggestive of a tolero- genic host immune response. Haematologica. 2010;95:440-448. doi:10.3324/haematol.2009.009647 The Online Supplementary Tables S1-5 are in separate PDF files Supplementary Design and Methods One microgram of total RNA was reverse transcribed using random primers and SuperScript II (Invitrogen, Merelbeke, Validation of microarray results by real-time quantitative Belgium), as recommended by the manufacturer. Relative reverse transcriptase polymerase chain reaction quantification was subsequently performed using the compar- Ten genes measured by microarray gene expression profil- ative CT method (see User Bulletin #2: Relative Quantitation ing were validated by real-time quantitative reverse transcrip- of Gene Expression, Applied Biosystems).
    [Show full text]
  • Fluid Biomarkers in Frontotemporal Dementia: Past, Present and Future
    Neurodegeneration J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2020-323520 on 13 November 2020. Downloaded from Review Fluid biomarkers in frontotemporal dementia: past, present and future Imogen Joanna Swift ,1 Aitana Sogorb- Esteve,1,2 Carolin Heller ,1 Matthis Synofzik,3,4 Markus Otto ,5 Caroline Graff,6,7 Daniela Galimberti ,8,9 Emily Todd,2 Amanda J Heslegrave,1 Emma Louise van der Ende ,10 John Cornelis Van Swieten ,10 Henrik Zetterberg,1,11 Jonathan Daniel Rohrer 2 ► Additional material is ABSTRACT into a behavioural form (behavioural variant fron- published online only. To view, The frontotemporal dementia (FTD) spectrum of totemporal dementia (bvFTD)), a language variant please visit the journal online (primary progressive aphasia (PPA)) and a motor (http:// dx. doi. org/ 10. 1136/ neurodegenerative disorders includes a heterogeneous jnnp- 2020- 323520). group of conditions. However, following on from a series presentation (either FTD with amyotrophic lateral of important molecular studies in the early 2000s, major sclerosis (FTD- ALS) or an atypical parkinsonian For numbered affiliations see advances have now been made in the understanding disorder). Neuroanatomically, the FTD spectrum end of article. of the pathological and genetic underpinnings of the is characteristically associated with dysfunction and disease. In turn, alongside the development of novel neuronal loss in the frontal and temporal lobes, but Correspondence to more widespread cortical, subcortical, cerebellar Dr Jonathan Daniel Rohrer, methodologies for measuring proteins and other Dementia Research molecules in biological fluids, the last 10 years have and brainstem involvement is now recognised. Centre, Department of seen a huge increase in biomarker studies within FTD.
    [Show full text]
  • Uncorrected Proof
    Progress in Neurobiology xxx (2018) xxx-xxx Contents lists available at ScienceDirect Progress in Neurobiology journal homepage: www.elsevier.com Review article Oligodendrogliopathy in neurodegenerative diseases with abnormal protein aggregates: The forgotten partner Isidro Ferrera⁠ ,⁠ b⁠ ,⁠ c⁠ ,⁠ d⁠ ,⁠ ⁎⁠ a Department of Pathology and Experimental Therapeutics, University of Barcelona, Hospitalet de Llobregat, Spain b Service of Pathology, Bellvitge University Hospital, IDIBELL, Hospitalet de Llobregat, Spain c CIBERNED (Biomedical Network Research Centre of Neurodegenerative Diseases), Institute of Health Carlos III, Spain d Institute of Neurosciences, University of Barcelona, Spain PROOF ARTICLE INFO ABSTRACT Keywords: Oligodendrocytes are in contact with neurons, wrap axons with a myelin sheath that protects their structural Oligodendrocytes integrity, and facilitate nerve conduction. Oligodendrocytes also form a syncytium with astrocytes which in- Multiple system atrophy teracts with neurons, promoting reciprocal survival mediated by activity and by molecules involved in energy Lewy body diseases metabolism and trophism. Therefore, oligodendrocytes are key elements in the normal functioning of the cen- Tauopathy tral nervous system. Oligodendrocytes are affected following different insults to the central nervous system Alzheimer’s disease including ischemia, traumatism, and inflammation. The term oligodendrogliopathy highlights the prominent Amyotrophic lateral sclerosis Frontotemporal lobar degeneration role of altered oligodendrocytes
    [Show full text]
  • Differential Regulation of Progranulin Derived Granulin Peptides Tingting
    bioRxiv preprint doi: https://doi.org/10.1101/2021.01.08.425959; this version posted January 9, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Differential regulation of progranulin derived granulin peptides Tingting Zhang1, Huan Du1, Mariela Nunez Santos1, Xiaochun Wu1, Thomas Reinheckel2 and Fenghua Hu1# 1Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA 2Institute of Molecular Medicine and Cell Research, Medical Faculty and BIOSS Centre for Biological Signaling Studies, Albert-Ludwigs-University Freiburg, 79104, Freiburg, Germany *Running Title: Differential regulation of granulin peptides #To whom correspondence should be addressed: Fenghua Hu, 345 Weill Hall, Ithaca, NY 14853, TEL: 607- 2550667, FAX: 607-2555961, Email: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/2021.01.08.425959; this version posted January 9, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). PGRN is comprised of 7.5 granulin repeats and the precursor is processed into individual granulin peptides by lysosome proteases. The granulin peptides are also haplo-insufficient in FTLD and proposed to possess unique functions. However, very little is known about the levels and regulations of each granulin peptide in the lysosome due to the lack of reagents to specifically detect each individual granulin peptide. Here we report the generation and characterization of antibodies specific to each granulin peptide.
    [Show full text]
  • Erlotinib Overcomes Paclitaxel-Resistant Cancer Stem
    Lv et al. Oncogenesis (2019) 8:70 https://doi.org/10.1038/s41389-019-0179-2 Oncogenesis ARTICLE Open Access Erlotinib overcomes paclitaxel-resistant cancer stem cells by blocking the EGFR-CREB/GRβ-IL-6 axis in MUC1-positive cervical cancer Yaping Lv1, Wei Cang2,QuanfuLi1, Xiaodong Liao1,MengnaZhan3,HuayunDeng1, Shengze Li1,WeiJin1,ZhiPang1, Xingdi Qiu2, Kewen Zhao4,GuoqiangChen4,LihuaQiu2 and Lei Huang1 Abstract Cancer stem cells (CSCs) are often enriched after chemotherapy and contribute to tumor relapse. While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are widely used for the treatment of diverse types of cancer, whether EGFR-TKIs are effective against chemoresistant CSCs in cervical cancer is largely unknown. Here, we reveal that EGFR correlates with reduced disease-free survival in cervical cancer patients with chemotherapy. Erlotinib, an EGFR-TKI, effectively impedes CSCs enrichment in paclitaxel-resistant cells through inhibiting IL-6. In this context, MUC1 induces CSCs enrichment in paclitaxel-resistant cells via activation of EGFR, which directly enhances IL-6 transcription through cAMP response element-binding protein (CREB) and glucocorticoid receptor β (GRβ). Treatment with erlotinib sensitizes CSCs to paclitaxel therapy both in vitro and in vivo. More importantly, positive correlations between the expressions of MUC1, EGFR, and IL-6 were found in 20 cervical cancer patients after chemotherapy. Mining TCGA data sets also uncovered the expressions of MUC1-EGFR-IL-6 correlates with poor disease-free survival in chemo-treated cervical cancer patients. Collectively, our work has demonstrated that the MUC1-EGFR-CREB/GRβ axis 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; stimulates IL-6 expression to induce CSCs enrichment and importantly, this effect can be abrogated by erlotinib, uncovering a novel strategy to treat paclitaxel-resistant cervical cancer.
    [Show full text]
  • Progranulin and the Receptor Tyrosine Kinase Epha2, Partners in Crime?
    JCB: SpotlightReview Progranulin and the receptor tyrosine kinase EphA2, partners in crime? Babykumari Chitramuthu1,2 and Andrew Bateman1,2 1Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada 2Centre for Translational Biology, Platform in Experimental Therapeutics and Metabolism, McGill University Health Centre Research Institute, Montreal, QC H4A 3J1, Canada Progranulin is a secreted protein with roles in of biological processes (Toh et al., 2011). It has growth fac- tumorigenesis, inflammation, and neurobiology, but its tor–like properties, stimulating cell proliferation, motility, and survival. It promotes tumorigenesis in vivo, is overexpressed signaling receptors have remained unclear. In this issue, in many cancers, and, as with EphA2, its expression often cor- Neill et al. (2016. J. Cell Biol. https​://doi​.org​/10​.1083​/ relates with more invasive tumors and poor patient outcomes jcb​.201603079) identify the tyrosine kinase EphA2 as a (Zhang and Bateman, 2011). It is angiogenic. Progranulin mod- strong candidate for such a receptor, providing insight ulates inflammation, with progranulin knockout mice display- ing a highly overblown inflammatory response. The loss of a into progranulin and EphA2 signaling. single allele of GRN in humans results in progressive loss of neurons in the frontal and temporal cortex that manifests clin- Occasionally, a paper brings together two seemingly unrelated ically as frontotemporal dementia (Petkau and Leavitt, 2014). strands of research in a new and illuminating fashion. In this Surprisingly, the loss of both GRN alleles does not result in issue, Neill et al. do just that by demonstrating that the EphA2 worsened frontotemporal dementia, as might be expected, but receptor tyrosine kinase is a functional receptor for the secreted instead in a neuronal lysosomal storage disease called neuro- glycoprotein progranulin, a protein that is totally unrelated to nal ceroid lipofuscinosis (Smith et al., 2012).
    [Show full text]
  • Differential Regulation of Progranulin Derived Granulin Peptides Tingting
    bioRxiv preprint doi: https://doi.org/10.1101/2021.01.08.425959; this version posted January 14, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Differential regulation of progranulin derived granulin peptides Tingting Zhang1, Huan Du1, Mariela Nunez Santos1, Xiaochun Wu1, Thomas Reinheckel2 and Fenghua Hu1# 1Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA 2Institute of Molecular Medicine and Cell Research, Medical Faculty and BIOSS Centre for Biological Signaling Studies, Albert-Ludwigs-University Freiburg, 79104, Freiburg, Germany *Running Title: Differential regulation of granulin peptides #To whom correspondence should be addressed: Fenghua Hu, 345 Weill Hall, Ithaca, NY 14853, TEL: 607- 2550667, FAX: 607-2555961, Email: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/2021.01.08.425959; this version posted January 14, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract Haploinsufficiency of progranulin (PGRN) is a leading cause of frontotemporal lobar degeneration (FTLD). PGRN is comprised of 7.5 granulin repeats and is processed into individual granulin peptides in the lysosome. However, very little is known about the levels and regulations of individual granulin peptides due to the lack of specific antibodies. Here we report the generation and characterization of antibodies specific to each granulin peptide. We found that the levels of granulins C, E and F are differentially regulated compared to granulins A and B.
    [Show full text]
  • Early Lysosomal Maturation Deficits in Microglia Triggers Enhanced Lysosomal Activity in Other Brain Cells of Progranulin Knockout Mice Julia K
    Götzl et al. Molecular Neurodegeneration (2018) 13:48 https://doi.org/10.1186/s13024-018-0281-5 RESEARCH ARTICLE Open Access Early lysosomal maturation deficits in microglia triggers enhanced lysosomal activity in other brain cells of progranulin knockout mice Julia K. Götzl1†, Alessio-Vittorio Colombo2†, Katrin Fellerer1†, Anika Reifschneider1, Georg Werner1, Sabina Tahirovic2, Christian Haass1,2,3* and Anja Capell1* Abstract Background: Heterozygous loss-of-function mutations in the progranulin gene (GRN) lead to frontotemporal lobar degeneration (FTLD) while the complete loss of progranulin (PGRN) function results in neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Thus the growth factor-like protein PGRN may play an important role in lysosomal degradation. In line with a potential lysosomal function, PGRN is partially localized and processed in lysosomes. In the central nervous system (CNS), PGRN is like other lysosomal proteins highly expressed in microglia, further supporting an important role in protein degradation. We have previously reported that cathepsin (Cat) D is elevated in GRN-associated FTLD patients and Grn knockout mice. However, the primary mechanism that causes impaired protein degradation and elevated CatD levels upon PGRN deficiency in NCL and FTLD remains unclear. Methods: mRNA expression analysis of selected lysosomal hydrolases, lysosomal membrane proteins and autophagy- related genes was performed by NanoString nCounter panel. Protein expression, maturation and in vitro activity of Cat D, B and L in mouse embryonic fibroblasts (MEF) and brains of Grn knockout mice were investigated. To selectively characterize microglial and non-microglial brain cells, an acutely isolated microglia fraction using MACS microbeads (Miltenyi Biotec) conjugated with CD11b antibody and a microglia-depleted fraction were analyzed for protein expression and maturation of selected cathepsins.
    [Show full text]