IPF fibroblasts are desensitized to type I collagen matrix-induced cell death by suppressing low autophagy via aberrant Akt/mTOR kinases.
Identifieur interne : 000247 ( Ncbi/Checkpoint ); précédent : 000246; suivant : 000248IPF 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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pubmed:24728102Le document en format XML
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<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>
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<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>
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<term>Protéines proto-oncogènes c-akt (métabolisme)</term>
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<term>Phagosomes</term>
<term>Protéines proto-oncogènes c-akt</term>
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<term>Cell Survival</term>
<term>Enzyme Activation</term>
<term>Humans</term>
<term>Protein Multimerization</term>
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<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>
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