Table of Contents
01 April 2018; volume 10, issue 4
News & Views
- Co‐targeting driver pathways in prostate cancer: two birds with one stone
Co‐targeting strategies strive to improve cancer outcomes by combining therapies under contextualized genetic and environmental conditions that selectively target exploitable alterations in tumor cells. Adaptive survival pathways triggered by inhibition of driver genes in the androgen receptor (AR) or PI3K/AKT pathways are of great interest, since they are among the most frequently altered in castrate‐resistant prostate cancer (CRPC). Unfortunately, negative feedback loops exist between the AR and PI3K/AKT pathways such that targeting AR leads to activation of PI3K/AKT signaling, while PI3K/AKT pathway inhibition leads to increased AR transcriptional activity. Hence, targeting both pathways provides an opportunity for conditional lethality and a high therapeutic index. In this issue of EMBO Molecular Medicine, Yan et al (2018) present an elegant study showing that histone deacetylase 3 (HDAC3) acts as a common upstream activator of both AR and AKT signaling pathways, and use HDAC3 inhibitors as a monotherapy to co‐target two major pathways driving CRPC growth.
See also: Y Yan et al (April 2018)
In this issue of EMBO Molecular Medicine, M. Gleave and A. Zoubeidi discuss a research article by Yan et al that provides a new approach to inhibit prostate cancer via targeting of a common upstream activator of both androgen receptor and AKT pathways.
EMBO Mol Med (2018) 10: e8928
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Research Articles
- Dual inhibition of AKT‐mTOR and AR signaling by targeting HDAC3 in PTEN‐ or SPOP‐mutated prostate cancer
- Yuqian Yan1,2,†,
- Jian An2,13,†,
- Yinhui Yang2,3,†,
- Di Wu2,
- Yang Bai2,3,
- William Cao2,
- Linlin Ma2,4,
- Junhui Chen5,
- Zhendong Yu6,
- Yundong He2,
- Xin Jin2,
- Yunqian Pan2,
- Tao Ma7,
- Shangqian Wang8,
- Xiaonan Hou9,
- Saravut John Weroha9,
- R Jeffrey Karnes10,
- Jun Zhang11,
- Jennifer J Westendorf2,
- Liguo Wang7,
- Yu Chen8,
- Wanhai Xu3,
- Runzhi Zhu (runzhizhu1978{at}163.com)*,4,
- Dejie Wang (wdj5257{at}sina.com)*,1,2 and
- Haojie Huang (huang.haojie{at}mayo.edu)*,2,10,12
- 1Department of Gastroenterology, Jiangxi Institute of Gastroenterology and Hepatology, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- 2Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA
- 3Department of Urology, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- 4Center for Cell Therapy, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
- 5Department of Minimally Invasive Intervention, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
- 6Central Laboratory, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
- 7Department of Biomedical Statistics and Informatics, Mayo Clinic Cancer Center, Rochester, MN, USA
- 8Human Oncology and Pathogenesis Program, Memorial Sloan‐Kettering Cancer Center, New York, NY, USA
- 9Department of Oncology, Mayo Clinic College of Medicine, Rochester, MN, USA
- 10Department of Urology, Mayo Clinic College of Medicine, Rochester, MN, USA
- 11Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, USA
- 12Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN, USA
- 13Present Address: Dana‐Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- ↵*
Corresponding author. Tel: +86 511‐84405370; E‐mail: runzhizhu1978{at}163.com
Corresponding author. Tel: +86 79188692507, E‐mail: wdj5257{at}sina.com
Corresponding author. Tel: +1 507‐293‐1712, E‐mail: huang.haojie{at}mayo.edu
↵† These authors contributed equally to this work
Both AKT and AR signaling pathways are activated in PTEN‐deficient or SPOP‐mutated prostate cancers and inhibition of one pathway often activates the other. AKT and AR pathways in PTEN‐deficient or SPOP‐mutated prostate cancers are both inhibited by the same HDAC3 inhibitor RGFP966.
Synopsis
Both AKT and AR signaling pathways are activated in PTEN‐deficient or SPOP‐mutated prostate cancers and inhibition of one pathway often activates the other. AKT and AR pathways in PTEN‐deficient or SPOP‐mutated prostate cancers are both inhibited by the same HDAC3 inhibitor RGFP966.
HDAC3 is the only member of the class I/II HDAC family that regulates AKT phosphorylation and its expression correlates with AKT phosphorylation in prostate cancer patient specimens.
HDAC3 regulation of AKT phosphorylation is mediated by deacetylation of K14 and K20 residues on AKT and the function of HDAC3 in the cytoplasm.
Conditional knockout of Hdac3 gene blocks Pten deletion‐induced Akt activation, prostate tumorigenesis and progression, and overall survival of mice.
The selective HDAC3 inhibitor RGFP966 inhibits growth of both PTEN‐deficient and SPOP‐mutated prostate cancer cells by suppressing phosphorylation of AKT and its downstream effector kinases and AR expression.
EMBO Mol Med (2018) 10: e8478
- Received September 11, 2017.
- Revision received February 7, 2018.
- Accepted February 8, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Sprouty2 loss‐induced IL6 drives castration‐resistant prostate cancer through scavenger receptor B1
- Rachana Patel (r.patel{at}beatson.gla.ac.uk)*,1,
- Janis Fleming1,
- Ernest Mui2,
- Carolyn Loveridge2,
- Peter Repiscak2,
- Arnaud Blomme1,
- Victoria Harle2,
- Mark Salji2,
- Imran Ahmad1,2,
- Katy Teo2,
- Freddie C Hamdy3,
- Ann Hedley1,
- Niels van den Broek1,
- Gillian Mackay1,
- Joanne Edwards2,
- Owen J Sansom1 and
- Hing Y Leung (h.leung{at}beatson.gla.ac.uk)*,1,2
- 1Cancer Research UK Beatson Institute, Glasgow, UK
- 2Institute of Cancer Sciences, Glasgow, UK
- 3Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Headington, Oxford, UK
- ↵*
Corresponding author. Tel: +44 141 330 8170; E‐mail: r.patel{at}beatson.gla.ac.uk
Corresponding author. Tel: +44 141 330 3658; E‐mail: h.leung{at}beatson.gla.ac.uk
Tumour‐induced IL6 modulates host lipid metabolism to drive treatment‐resistant castration‐resistant prostate cancer (CRPC). Blocking tumoral cholesterol uptake using SRB1 antagonist or restoring systemic cholesterol homeostasis using statins decreases treatment resistance.
Synopsis
Tumour‐induced IL6 modulates host lipid metabolism to drive treatment‐resistant castration‐resistant prostate cancer (CRPC). Blocking tumoral cholesterol uptake using SRB1 antagonist or restoring systemic cholesterol homeostasis using statins decreases treatment resistance.
SPRY2 deficiency drives androgen self‐sufficient form CRPC though HER2‐mediated IL6.
IL6 mediates tumoural androgen synthesis by inducing HSD3B1 expression.
Systemic IL6 mediates host adipose lipolysis and stimulates hepatic cholesterol biosynthesis leading to elevated levels of circulating cholesterol.
SPRY2 loss‐induced IL6 mediates tumoural cholesterol uptake through the HDL receptor SRB1 to drive CRPC.
Using a clinically safe SRB1 antagonist (ITX5061) decreased treatment‐resistance.
EMBO Mol Med (2018) 10: e8347
- Received August 4, 2017.
- Revision received February 9, 2018.
- Accepted February 20, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Inhibition of DDR1‐BCR signalling by nilotinib as a new therapeutic strategy for metastatic colorectal cancer
- Maya Jeitany1,†,
- Cédric Leroy1,2,3,†,
- Priscillia Tosti1,†,
- Marie Lafitte1,
- Jordy Le Guet1,
- Valérie Simon1,
- Debora Bonenfant2,
- Bruno Robert4,
- Fanny Grillet5,
- Caroline Mollevi4,
- Safia El Messaoudi4,
- Amaëlle Otandault4,
- Lucile Canterel‐Thouennon4,
- Muriel Busson4,
- Alain R Thierry4,
- Pierre Martineau4,
- Julie Pannequin5,
- Serge Roche (serge.roche{at}crbm.cnrs.fr)*,1,† and
- Audrey Sirvent (audrey.sirvent{at}crbm.cnrs.fr)*,1,†
- 1CRBM, CNRS, University Montpellier, Montpellier, France
- 2Novartis Institutes for Biomedical Research, Postfach, Basel, Switzerland
- 3Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
- 4IRCM, INSERM, University Montpellier, Montpellier, France
- 5IGF, CNRS, INSERM, University Montpellier, Montpellier, France
- ↵*
Corresponding author. Tel: +33 434359520; E‐mail: serge.roche{at}crbm.cnrs.fr
Corresponding author. Tel: +33 434359503; E‐mail: audrey.sirvent{at}crbm.cnrs.fr
↵† These authors contributed equally to this work
The clinical management of metastatic colorectal cancer (mCRC) faces major challenges. Targeting the receptor for collagens DDR1 by nilotinib inhibits mCRC cells properties and paves the way to a new therapeutic strategy for mCRC.
Synopsis
The clinical management of metastatic colorectal cancer (mCRC) faces major challenges. Targeting the receptor for collagens DDR1 by nilotinib inhibits mCRC cells properties and paves the way to a new therapeutic strategy for mCRC.
DDR1 tyrosine kinase activity promotes colorectal cancer cell invasion and metastatic properties in nude mice.
BCR is a central substrate of DDR1.
DDR1 activation maintains a high level of β‐catenin transcriptional activity necessary for cell invasion and metastatic progression.
DDR1 pharmacological inhibition by nilotinib inhibits colorectal cancer cell invasion and metastatic properties in nude mice.
Nilotinib may be of clinical interest for treatment of metastatic colorectal cancer.
EMBO Mol Med (2018) 10: e7918
- Received April 19, 2017.
- Revision received January 10, 2018.
- Accepted January 15, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- An FGFR3/MYC positive feedback loop provides new opportunities for targeted therapies in bladder cancers
- Mélanie Mahe1,2,†,
- Florent Dufour1,2,†,
- Hélène Neyret‐Kahn1,2,
- Aura Moreno‐Vega1,2,
- Claire Beraud3,
- Mingjun Shi1,2,
- Imene Hamaidi4,
- Virginia Sanchez‐Quiles1,2,
- Clementine Krucker1,2,
- Marion Dorland‐Galliot1,2,
- Elodie Chapeaublanc1,2,
- Remy Nicolle1,2,
- Hervé Lang4,
- Celio Pouponnot5,6,7,
- Thierry Massfelder8,
- François Radvanyi1,2 and
- Isabelle Bernard‐Pierrot (isabelle.bernard-pierrot{at}curie.fr)*,1,2
- 1Institut Curie, CNRS, UMR144, Equipe Labellisée Ligue contre le Cancer, PSL Research University, Paris, France
- 2CNRS, UMR144, Sorbonne Universités UPMC Université Paris 06, Paris, France
- 3UROLEAD SAS, School of Medicine, Strasbourg, France
- 4Department of Urology, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
- 5Institut Curie, Orsay, France
- 6CNRS UMR3347 Centre Universitaire, Orsay, France
- 7INSERM U1021 Centre Universitaire, Orsay, France
- 8INSERM UMR_S1113, Section of Cell Signalization and Communication in Kidney and Prostate Cancer, School of Medicine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), INSERM and University of Strasbourg, Strasbourg, France
- ↵*Corresponding author. Tel: +33 1 42 34 63 40; Fax: +33 1 42 34 63 49; E‐mail: isabelle.bernard-pierrot{at}curie.fr
↵† These authors contributed equally to this work
In bladder carcinoma, alterations of FGFR3 receptor are often observed and lead to constitutive activation and oncogene addiction, which can be targeted with a pan‐FGFR inhibitor. Our identification and characterization of a FGFR3/MYC positive feedback loop opens new avenues for targeted therapies.
Synopsis
In bladder carcinoma, alterations of FGFR3 receptor are often observed and lead to constitutive activation and oncogene addiction, which can be targeted with a pan‐FGFR inhibitor. Our identification and characterization of a FGFR3/MYC positive feedback loop opens new avenues for targeted therapies.
MYC is a key master regulator of proliferation activated by aberrantly activated FGFR3.
FGFR3‐dependent MYC accumulation is dependent on p38, which regulates MYC mRNA levels, and AKT, which stabilizes MYC protein.
FGFR3 is directly targeted by MYC.
Disrupting the FGFR3/MYC loop using FGFR3, p38, AKT, or BET bromodomain inhibitors decreases cell viability and tumor growth in FGFR3‐dependent cell lines.
Evidence for the relevance of the FGFR3/MYC feedback loop to human tumors is provided by the decrease in both FGFR3 and MYC levels induced by a pan‐FGFR inhibitor in a PDX model bearing an FGFR3 mutation, and by the positive correlation between MYC and FGFR3 levels in human tumors with FGFR3 mutations.
EMBO Mol Med (2018) 10: e8163
- Received June 15, 2017.
- Revision received January 19, 2018.
- Accepted January 23, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Tranilast directly targets NLRP3 to treat inflammasome‐driven diseases
- Yi Huang1,2,†,
- Hua Jiang1,†,
- Yun Chen3,
- Xiaqiong Wang1,
- Yanqing Yang4,
- Jinhui Tao5,
- Xianming Deng3,
- Gaolin Liang6,
- Huafeng Zhang1,2,
- Wei Jiang (ustcjw{at}ustc.edu.cn)*,1 and
- Rongbin Zhou (zrb1980{at}ustc.edu.cn)*,1,2
- 1Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Sciences, Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, China
- 2Innovation Center for Cell Signaling Network, University of Science and Technology of China, Hefei, China
- 3State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
- 4Department of Clinical Laboratory, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
- 5Department of Rheumatology & Immunology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui, China
- 6CAS Key Laboratory of Soft Matter Chemistry, Department of Chemistry, University of Science and Technology of China, Hefei, China
- ↵*
Corresponding author. Tel: +86‐551‐63600125; E‐mail: ustcjw{at}ustc.edu.cn
Corresponding author. Tel: +86‐551‐63600302; Fax: +86‐551‐63600831; E‐mail: zrb1980{at}ustc.edu.cn
↵† These authors contributed equally to this work
Tranilast (TR), an anti‐allergic clinical drug, is here reported as a NLRP3 inflammasome inhibitor with beneficial effects for NLRP3‐driven diseases. By direct binding to NLRP3, it inhibits its oligomerization and subsequent inflammasome assembly, caspase‐1 activation and IL‐1β production.
Synopsis
Tranilast (TR), an anti‐allergic clinical drug, is here reported as a NLRP3 inflammasome inhibitor with beneficial effects for NLRP3‐driven diseases. By direct binding to NLRP3, it inhibits its oligomerization and subsequent inflammasome assembly, caspase‐1 activation and IL‐1β production.
TR specifically inhibits NLRP3 inflammasome activation in both human and mouse cells.
TR binds to NLRP3 and inhibits its oligomerization and inflammasome complex formation.
TR has remarkable preventive or therapeutic effects on the mouse models of NLRP3‐driven diseases.
EMBO Mol Med (2018) 10: e8689
- Received November 14, 2017.
- Revision received February 10, 2018.
- Accepted February 19, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Role of NKp46+ natural killer cells in house dust mite‐driven asthma
- Eline Haspeslagh1,2,†,
- Mary J van Helden1,3,8,†,
- Kim Deswarte1,3,
- Sofie De Prijck1,2,
- Justine van Moorleghem1,3,
- Louis Boon4,
- Hamida Hammad1,3,
- Eric Vivier5,6 and
- Bart N Lambrecht (bart.lambrecht{at}ugent.be)*,1,3,7
- 1Immunoregulation and Mucosal Immunology, VIB Center for Inflammation Research, Ghent, Belgium
- 2Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- 3Department of Internal Medicine, Ghent University, Ghent, Belgium
- 4Bioceros BV, Utrecht, The Netherlands
- 5Centre d'Immunologie de Marseille‐Luminy, Inserm, CNRS, Aix Marseille Université Parc Scientifique & Technologique de Luminy, Marseille Cedex, France
- 6Service d'Immunologie, Hôpital de la Timone, Assistance Publique‐Hôpitaux de Marseille, Marseille, France
- 7Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands
- 8Present Address: Aduro Biotech Europe, Oss, The Netherlands
- ↵*Corresponding author. Tel: +32 9 33 13 601; Fax: +32 9 221 76 73; E‐mail: bart.lambrecht{at}ugent.be
↵† These authors contributed equally to this work
The function of NK cells in allergic asthma development has been confusing, as targeting strategies with different specificities have generated conflicting results. Here, conventional NK cells are genetically and specifically depleted and shown to be dispensable for asthma development in mice.
Synopsis
The function of NK cells in allergic asthma development has been confusing, as targeting strategies with different specificities have generated conflicting results. Here, conventional NK cells are genetically and specifically depleted and shown to be dispensable for asthma development in mice.
Allergic asthma to house dust mite or ovalbumin can be induced in genetically engineered Ncr1‐DTA mice that constitutively lack all NKp46+ cells.
The asthma phenotype is neither affected by temporarily depleting NK cells in Ncr1‐DTR mice, nor by antibody‐mediated depletion of NK1.1+ or asialoGM1+ cells.
Antibody‐mediated blocking or genetic depletion of the NKG2D receptor does not influence allergic asthma development.
EMBO Mol Med (2018) 10: e8657
- Received November 6, 2017.
- Revision received January 12, 2018.
- Accepted January 18, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Counteracting the effects of TNF receptor‐1 has therapeutic potential in Alzheimer's disease
- Sophie Steeland1,2,†,
- Nina Gorlé1,2,†,
- Charysse Vandendriessche1,2,†,
- Sriram Balusu1,2,
- Marjana Brkic1,2,3,
- Caroline Van Cauwenberghe1,2,
- Griet Van Imschoot1,2,
- Elien Van Wonterghem1,2,
- Riet De Rycke1,2,
- Anneke Kremer1,2,4,
- Saskia Lippens1,2,4,
- Edward Stopa5,6,
- Conrad E Johanson6,
- Claude Libert1,2 and
- Roosmarijn E Vandenbroucke (roosmarijn.vandenbroucke{at}irc.vib-ugent.be)*,1,2
- 1VIB Center for Inflammation Research, Ghent, Belgium
- 2Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- 3Department of Neurobiology, Institute for Biological Research, University of Belgrade, Belgrade, Republic of Serbia
- 4VIB BioImaging Core, Ghent, Belgium
- 5Department of Pathology, Rhode Island Hospital, Providence, Rhode Island, USA
- 6Department of Neurosurgery, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
- ↵*Corresponding author. Tel: +32 (0)9 331 35 87; Fax: +32 (0)9 221 76 73; E‐mail: roosmarijn.vandenbroucke{at}irc.vib-ugent.be
↵† These authors contributed equally to this work
Increased TNF/TNFR1 signaling plays a detrimental role in Alzheimer's disease pathology and is associated with morphological alterations at the choroid plexus in patients and mice, and neuroinflammation. Blocking TNFR1 signaling prevents cognitive decline in Alzheimer's disease mouse models.
Synopsis
Increased TNF/TNFR1 signaling plays a detrimental role in Alzheimer's disease pathology and is associated with morphological alterations at the choroid plexus in patients and mice, and neuroinflammation. Blocking TNFR1 signaling prevents cognitive decline in Alzheimer's disease mouse models.
TNF/TNFR1 signaling is activated in the choroid plexus of late‐stage Alzheimer's disease patients.
Increased TNFR1 signaling contributes to morphological alterations in choroid plexus epithelial cells.
TNFR1 deficiency prevents neuroinflammation and amyloidogenesis, and reduces microgliosis in Alzheimer's disease mouse models.
Genetic and pharmacological blockage of TNFR1 signaling prevents cognitive decline in Alzheimer's disease mouse models.
EMBO Mol Med (2018) 10: e8300
- Received July 21, 2017.
- Revision received January 10, 2018.
- Accepted January 18, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- An allosteric inhibitor of Mycobacterium tuberculosis ArgJ: Implications to a novel combinatorial therapy
- Archita Mishra1,
- Ashalatha S Mamidi1,
- Raju S Rajmani2,
- Ananya Ray1,
- Rajanya Roy1 and
- Avadhesha Surolia (surolia{at}mbu.iisc.ernet.in)*,1
- 1Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India
- 2Microbiology and Cell Biology, CIDR, Indian Institute of Science, Bangalore, India
- ↵*Corresponding author. Tel: +80 2293 2714; E‐mail: surolia{at}mbu.iisc.ernet.in
Mycobacterium tuberculosis (Mtb) is an infectious pathogen claiming millions of lives worldwide. This study identifies a novel inhibitor against the MtArgJ enzyme of the arginine biosynthesis pathway, essential for pathogenicity and survival, and establishes its efficacy in pre‐clinical models.
Synopsis
Mycobacterium tuberculosis (Mtb) is an infectious pathogen claiming millions of lives worldwide. This study identifies a novel inhibitor against the MtArgJ enzyme of the arginine biosynthesis pathway, essential for pathogenicity and survival, and establishes its efficacy in pre‐clinical models.
In silico and in vitro FDA approved drugs were screened to target an allosteric site on MtArgJ and Pranlukast (PRK) was identified as a potent inhibitor.
PRK treatment reduced Mtb survival both in vitro and in infected macrophages.
PRK efficiently reduced the lung associated Mtb burden and tubercular granulomas in mouse models of infection.
PRK inhibited Mtb survival in vivo by dual mechanisms, through targeting arginine biosynthesis of the pathogen and inhibiting the Mtb pro‐survival signaling (5‐LO) in the host.
PRK potentiated the effect of Rifampicin (Rif) in vivo, thereby introducing a novel combination (Rif with PRK) towards therapeutic regime for tuberculosis.
EMBO Mol Med (2018) 10: e8038
- Received May 16, 2017.
- Revision received January 19, 2018.
- Accepted January 26, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis
- Marianna Parlato1,2,
- Fabienne Charbit‐Henrion1,2,3,4,
- Jie Pan5,
- Claudio Romano2,6,
- Rémi Duclaux‐Loras1,2,3,
- Marie‐Helene Le Du7,
- Neil Warner5,
- Paola Francalanci8,
- Julie Bruneau3,9,
- Marc Bras10,
- Mohammed Zarhrate11,
- Bernadette Bègue1,2,
- Nicolas Guegan1,3,
- Sabine Rakotobe1,2,
- Nathalie Kapel12,
- Paola De Angelis8,
- Anne M Griffiths5,
- Karoline Fiedler5,
- Eileen Crowley5,
- Frank Ruemmele1,2,3,4,
- Aleixo M Muise (aleixo.muise{at}sickkids.ca)*,5,13,14,† and
- Nadine Cerf‐Bensussan (nadine.cerf-bensussan{at}inserm.fr)*,1,2,3,†
- 1INSERM, UMR1163, Laboratory of Intestinal Immunity and Institut Imagine, Paris, France
- 2 GENIUS group from ESPGHAN
- 3Université Paris Descartes‐Sorbonne Paris Cité, Paris, France
- 4Department of Pediatric Gastroenterology, Assistance Publique‐Hôpitaux de Paris Hôpital Necker‐Enfants Malades, Paris, France
- 5SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada
- 6Unit of Pediatrics, Department of Human Pathology in Adulthood and Childhood “G. Barresi”, University of Messina, Messina, Italy
- 7Department of Biochemistry, Biophysics and Structural Biology, Institute for Integrative Biology of the Cell (I2BC), CEA, UMR 9198 CNRS, Université Paris‐Sud, Gif‐sur‐Yvette, France
- 8Digestive Endoscopy and Surgery Unit and Pathology Unit Bambino Gesù Children Hospital, IRCCS, Rome, Italy
- 9Department of Pathology, Necker‐Enfants Malades Hospital Assistance Publique‐Hôpitaux de Paris, Paris, France
- 10Bioinformatics Platform, Université Paris‐Descartes‐Paris Sorbonne Centre and Institut Imagine, Paris, France
- 11Genomic Platform, INSERM, UMR1163, Imagine Institute, Paris Descartes‐Sorbonne Paris Cite University, Paris, France
- 12Department of Functional Coprology, Pitié Salpêtrière Hospital Assistance publique‐Hôpitaux de Paris (AP‐HP), Paris, France
- 13Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
- 14Department of Biochemistry, Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- ↵*
Corresponding author. Tel: +1 416 813 7735; E‐mail: aleixo.muise{at}sickkids.ca
Corresponding author. Tel: +33 1 4275 4288; E‐mail: nadine.cerf-bensussan{at}inserm.fr
↵† These authors contributed equally to this work
Whole‐exome sequencing in two unrelated patients with severe intestinal inflammation identified loss‐of‐function mutations in ALPI, a brush border enzyme which detoxifies lipopolysaccharides (LPS) through dephosphorylation of its lipid A moiety, linking ALPI deficiency to inflammatory bowel diseases.
Synopsis
Whole‐exome sequencing in two unrelated patients with severe intestinal inflammation identified loss‐of‐function mutations in ALPI, a brush border enzyme which detoxifies lipopolysaccharides (LPS) through dephosphorylation of its lipid A moiety, linking ALPI deficiency to inflammatory bowel diseases.
Structural modelling of ALPI mutants indicated that affected residues are critical for inter‐subunit interactions.
Heterologous expression of ALPI mutants in HEK293T cells demonstrated that all mutations were loss of function and impaired either stability or catalytic activity of ALPI which could no more detoxify LPS.
ALPI expression was strongly decreased in small intestinal biopsies from ALPI deficient patients.
ALPI activity was undetectable in ALPI deficiency patient's stools.
EMBO Mol Med (2018) 10: e8483
- Received September 13, 2017.
- Revision received February 19, 2018.
- Accepted February 19, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Commentary
In pediatric cancer, we advocate for trio sequencing of the child and its parents. This method can have substantial implications for cancer prevention in parents and siblings and even in more distant family members. It does not only help to identify a putative classical cancer predisposition syndrome in the index patient, but also detects the combinatorial effect of two independent risk variants in the same signaling pathway. This type of inheritance pattern could contribute to explaining the early occurrence of cancer in children and young adults and thereby inform early diagnosis, screening and preventive measures.
From identifying a putative classical cancer predisposition syndrome in the index patient, trio‐sequencing can also detect a potential combinatorial effect of two independent risk variants in the same signaling pathway. M. Kuhlen and A. Borkhardt explain here why they advocate for it.
EMBO Mol Med (2018) 10: e8641
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.