Differential responses to folic acid in an established keloid fibroblast cell line are mediated by JAK1/2 and STAT3

Autor: Ian A. Myles, Manoj Yadav, Alexandra F. Freeman, Katelyn J. McCann, Mohammadali E. Alishahedani
Jazyk: angličtina
Rok vydání: 2021
Předmět:
B Vitamins
Metabolic Processes
Ruxolitinib
Cell Lines
Scars
Mitochondrion
Biochemistry
Epithelium
Keloid
Animal Cells
Medicine and Health Sciences
Medicine
Glycolysis
STAT3
skin and connective tissue diseases
Energy-Producing Organelles
Cells
Cultured
Connective Tissue Cells
Multidisciplinary
biology
Organic Compounds
Vitamins
Mitochondria
Chemistry
Connective Tissue
Physical Sciences
Vitamin B Complex
Biological Cultures
medicine.symptom
Anatomy
Cellular Types
Cellular Structures and Organelles
Keloid disorder
medicine.drug
Research Article
Signal Transduction
STAT3 Transcription Factor
Cell Physiology
Science
Bioenergetics
Research and Analysis Methods
Folic Acid
Nitriles
Humans
Protein Kinase Inhibitors
business.industry
Organic Chemistry
Chemical Compounds
Biology and Life Sciences
Cell Biology
Janus Kinase 1
Fibroblasts
Janus Kinase 2
medicine.disease
Cell Metabolism
Biological Tissue
Metabolism
Pyrimidines
Keloids
Cancer research
biology.protein
Pyrazoles
Cultured Fibroblasts
Wound healing
business
Zdroj: PLoS ONE
PLoS ONE, Vol 16, Iss 3, p e0248011 (2021)
ISSN: 1932-6203
Popis: Keloids are a type of disordered scar formation which not only show heterogeneity between individuals and within the scar itself, but also share common features of hyperproliferation, abnormal extra-cellular matrix deposition and degradation, as well as altered expression of the molecular markers of wound healing. Numerous reports have established that cells from keloid scars display Warburg metabolism—a form of JAK2/STAT3-induced metabolic adaptation typical of rapidly dividing cells in which glycolysis becomes the predominant source of ATP over oxidative phosphorylation (OxPhos). Using the JAK1/2 inhibitor ruxolitinib, along with cells from patients with STAT3 loss of function (STA3 LOF; autosomal dominant hyper IgE syndrome) we examined the role of JAK/STAT signaling in the hyperproliferation and metabolic dysregulation seen in keloid fibroblasts. Although ruxolitinib inhibited hyperactivity in the scratch assay in keloid fibroblasts, it paradoxically exacerbated the hyper-glycolytic state, possibly by further limiting OxPhos via alterations in mitochondrial phosphorylated STAT3 (pSTAT3Ser727). In healthy volunteer fibroblasts, folic acid exposure recapitulated the exaggerated closure and hyper-glycolytic state of keloid fibroblasts through JAK1/2- and STAT3-dependent pathways. Although additional studies are needed before extrapolating from a representative cell line to keloids writ large, our results provide novel insights into the metabolic consequences of STAT3 dysfunction, suggest a possible role for folate metabolism in the pathogenesis of keloid scars, and offer in vitro pre-clinical data supporting considerations of clinical trials for ruxolitinib in keloid disorder.
Databáze: OpenAIRE
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