IPF fibroblasts are desensitized to type I collagen matrix-induced cell death by suppressing low autophagy via aberrant Akt/mTOR kinases.
Identifieur interne : 001024 ( Main/Exploration ); précédent : 001023; suivant : 001025IPF fibroblasts are desensitized to type I collagen matrix-induced cell death by suppressing low autophagy via aberrant Akt/mTOR kinases.
Auteurs : Richard Seonghun Nho [États-Unis] ; Polla Hergert [États-Unis]Source :
- PloS one [ 1932-6203 ] ; 2014.
Descripteurs français
- KwdFr :
- Activation enzymatique, Adénine (analogues et dérivés), Adénine (pharmacologie), Autophagie (), Chloroquine (pharmacologie), Collagène de type I (), Collagène de type I (métabolisme), Fibroblastes (métabolisme), Fibrose pulmonaire idiopathique (métabolisme), Humains, Lignée cellulaire, Multimérisation de protéines, Phagosomes (métabolisme), Prolifération cellulaire, Protéines proto-oncogènes c-akt (métabolisme), Survie cellulaire, Sérine-thréonine kinases TOR (métabolisme).
- MESH :
- analogues et dérivés : Adénine.
- métabolisme : Collagène de type I, Fibroblastes, Fibrose pulmonaire idiopathique, Phagosomes, Protéines proto-oncogènes c-akt, Sérine-thréonine kinases TOR.
- pharmacologie : Adénine, Chloroquine.
- Activation enzymatique, Autophagie, Collagène de type I, Humains, Lignée cellulaire, Multimérisation de protéines, Prolifération cellulaire, Survie cellulaire.
English descriptors
- KwdEn :
- Adenine (analogs & derivatives), Adenine (pharmacology), Autophagy (drug effects), Cell Line, Cell Proliferation, Cell Survival, Chloroquine (pharmacology), Collagen Type I (chemistry), Collagen Type I (metabolism), Enzyme Activation, Fibroblasts (metabolism), Humans, Idiopathic Pulmonary Fibrosis (metabolism), Phagosomes (metabolism), Protein Multimerization, Proto-Oncogene Proteins c-akt (metabolism), TOR Serine-Threonine Kinases (metabolism).
- MESH :
- chemical , analogs & derivatives : Adenine.
- chemical , chemistry : Collagen Type I.
- chemical , metabolism : Collagen Type I, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases.
- chemical , pharmacology : Adenine, Chloroquine.
- drug effects : Autophagy.
- metabolism : Fibroblasts, Idiopathic Pulmonary Fibrosis, Phagosomes.
- Cell Line, Cell Proliferation, Cell Survival, Enzyme Activation, Humans, Protein Multimerization.
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, lethal interstitial lung disease in which the aberrant PTEN/Akt axis plays a major role in conferring a survival phenotype in response to the cell death inducing properties of type I collagen matrix. The underlying mechanism by which IPF fibroblasts become desensitized to polymerized collagen, thereby eluding collagen matrix-induced cell death has not been fully elucidated. We hypothesized that the pathologically altered PTEN/Akt axis suppresses autophagy via high mTOR kinase activity, which subsequently desensitizes IPF fibroblasts to collagen matrix induced cell death. We found that the autophagosome marker LC3-2 expression is suppressed, while mTOR activity remains high when IPF fibroblasts are cultured on collagen. However, LC3-2 expression increased in response to IPF fibroblast attachment to collagen in the presence of rapamycin. In addition, PTEN over-expression or Akt inhibition suppressed mTOR activity, thereby increasing LC3-2 expression in IPF fibroblasts. Furthermore, the treatment of IPF fibroblasts over-expressing PTEN or dominant negative Akt with autophagy inhibitors increased IPF fibroblast cell death. Enhanced p-mTOR expression along with low LC3-2 expression was also found in myofibroblasts within the fibroblastic foci from IPF patients. Our data show that the aberrant PTEN/Akt/mTOR axis desensitizes IPF fibroblasts from polymerized collagen driven stress by suppressing autophagic activity, which produces a viable IPF fibroblast phenotype on collagen. This suggests that the aberrantly regulated autophagic pathway may play an important role in maintaining a pathological IPF fibroblast phenotype in response to collagen rich environment.
DOI: 10.1371/journal.pone.0094616
PubMed: 24728102
Affiliations:
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Minnesota</wicri:regionArea><placeName><region type="state">Minnesota</region></placeName></affiliation></author><author><name sortKey="Hergert, Polla" sort="Hergert, Polla" uniqKey="Hergert P" first="Polla" last="Hergert">Polla Hergert</name><affiliation wicri:level="2"><nlm:affiliation>Department of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, University of Minnesota, Minneapolis, Minnesota</wicri:regionArea><placeName><region type="state">Minnesota</region></placeName></affiliation></author></analytic><series><title level="j">PloS one</title><idno type="eISSN">1932-6203</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adenine (analogs & derivatives)</term><term>Adenine (pharmacology)</term><term>Autophagy (drug effects)</term><term>Cell Line</term><term>Cell Proliferation</term><term>Cell Survival</term><term>Chloroquine (pharmacology)</term><term>Collagen Type I (chemistry)</term><term>Collagen Type I (metabolism)</term><term>Enzyme Activation</term><term>Fibroblasts (metabolism)</term><term>Humans</term><term>Idiopathic Pulmonary Fibrosis (metabolism)</term><term>Phagosomes (metabolism)</term><term>Protein Multimerization</term><term>Proto-Oncogene Proteins c-akt (metabolism)</term><term>TOR Serine-Threonine Kinases (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Activation enzymatique</term><term>Adénine (analogues et dérivés)</term><term>Adénine (pharmacologie)</term><term>Autophagie ()</term><term>Chloroquine (pharmacologie)</term><term>Collagène de type I ()</term><term>Collagène de type I (métabolisme)</term><term>Fibroblastes (métabolisme)</term><term>Fibrose pulmonaire idiopathique (métabolisme)</term><term>Humains</term><term>Lignée cellulaire</term><term>Multimérisation de protéines</term><term>Phagosomes (métabolisme)</term><term>Prolifération cellulaire</term><term>Protéines proto-oncogènes c-akt (métabolisme)</term><term>Survie cellulaire</term><term>Sérine-thréonine kinases TOR (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Adenine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Collagen Type I</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Collagen Type I</term><term>Proto-Oncogene Proteins c-akt</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Adenine</term><term>Chloroquine</term></keywords><keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr"><term>Adénine</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Autophagy</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Fibroblasts</term><term>Idiopathic Pulmonary Fibrosis</term><term>Phagosomes</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Collagène de type I</term><term>Fibroblastes</term><term>Fibrose pulmonaire idiopathique</term><term>Phagosomes</term><term>Protéines proto-oncogènes c-akt</term><term>Sérine-thréonine kinases TOR</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Adénine</term><term>Chloroquine</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line</term><term>Cell Proliferation</term><term>Cell Survival</term><term>Enzyme Activation</term><term>Humans</term><term>Protein Multimerization</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Activation enzymatique</term><term>Autophagie</term><term>Collagène de type I</term><term>Humains</term><term>Lignée cellulaire</term><term>Multimérisation de protéines</term><term>Prolifération cellulaire</term><term>Survie cellulaire</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Idiopathic pulmonary fibrosis (IPF) is a chronic, lethal interstitial lung disease in which the aberrant PTEN/Akt axis plays a major role in conferring a survival phenotype in response to the cell death inducing properties of type I collagen matrix. The underlying mechanism by which IPF fibroblasts become desensitized to polymerized collagen, thereby eluding collagen matrix-induced cell death has not been fully elucidated. We hypothesized that the pathologically altered PTEN/Akt axis suppresses autophagy via high mTOR kinase activity, which subsequently desensitizes IPF fibroblasts to collagen matrix induced cell death. We found that the autophagosome marker LC3-2 expression is suppressed, while mTOR activity remains high when IPF fibroblasts are cultured on collagen. However, LC3-2 expression increased in response to IPF fibroblast attachment to collagen in the presence of rapamycin. In addition, PTEN over-expression or Akt inhibition suppressed mTOR activity, thereby increasing LC3-2 expression in IPF fibroblasts. Furthermore, the treatment of IPF fibroblasts over-expressing PTEN or dominant negative Akt with autophagy inhibitors increased IPF fibroblast cell death. Enhanced p-mTOR expression along with low LC3-2 expression was also found in myofibroblasts within the fibroblastic foci from IPF patients. Our data show that the aberrant PTEN/Akt/mTOR axis desensitizes IPF fibroblasts from polymerized collagen driven stress by suppressing autophagic activity, which produces a viable IPF fibroblast phenotype on collagen. This suggests that the aberrantly regulated autophagic pathway may play an important role in maintaining a pathological IPF fibroblast phenotype in response to collagen rich environment. </div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Minnesota</li></region></list><tree><country name="États-Unis"><region name="Minnesota"><name sortKey="Nho, Richard Seonghun" sort="Nho, Richard Seonghun" uniqKey="Nho R" first="Richard Seonghun" last="Nho">Richard Seonghun Nho</name></region><name sortKey="Hergert, Polla" sort="Hergert, Polla" uniqKey="Hergert P" first="Polla" last="Hergert">Polla Hergert</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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