IPF fibroblasts are desensitized to type I collagen matrix-induced cell death by suppressing low autophagy via aberrant Akt/mTOR kinases

• Published in: PloS one 2014-04, Vol.9 (4), p.e94616-e94616
• Main Authors: Nho, Richard Seonghun, Hergert, Polla
• Format: Article
• Language: English
• Subjects: Aberration; Adenine - analogs & derivatives; Adenine - pharmacology; AKT protein; Apoptosis; Autophagy; Autophagy - drug effects; Biology and life sciences; Cell death; Cell Line; Cell Proliferation; Cell Survival; Chloroquine - pharmacology; Collagen; Collagen (type I); Collagen Type I - chemistry; Collagen Type I - metabolism; Desensitization; Enzyme Activation; Fibroblasts; Fibroblasts - metabolism; Fibrosis; Genotype & phenotype; Health aspects; Humans; Idiopathic Pulmonary Fibrosis - metabolism; Kinases; Lung diseases; Medicine and Health Sciences; Mortality; Overexpression; Patients; Phagocytosis; Phagosomes - metabolism; Physiological aspects; Polymerization; Protein kinases; Protein Multimerization; Proteins; Proto-Oncogene Proteins c-akt - metabolism; PTEN protein; Pulmonary fibrosis; Rapamycin; Rodents; Studies; TOR protein; TOR Serine-Threonine Kinases - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0094616

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.