mTOR as a potential therapeutic target for treatment of keloids and excessive scars.
Keloid is a dermal fibroproliferative disorder characterized by excessive deposition of extracellular matrix (ECM) components such as collagen, glycoproteins and fibronectin. The mammalian target of rapamycin (mTOR) is a serine/theronine kinase which plays an important role in the regulation of metabolic processes and translation rates. Published reports have shown mTOR as regulator of collagen expression and its inhibition induces a decrease in ECM deposition. Our aim was to investigate the role of mTOR in keloid pathogenesis and investigate the effect of rapamycin on proliferating cell nuclear antigen (PCNA), cyclin D1, collagen, fibronectin and alpha-smooth muscle actin (alpha-SMA) expression in normal fibroblasts (NF) and keloid fibroblasts (KF). Tissue extracts obtained from keloid scar demonstrated elevated expression of mTOR, p70KDa S6 kinase (p70S6K) and their activated forms, suggesting an activated state in keloid scars. Serum stimulation highlighted the heightened responsiveness of KF to mitogens and the importance of mTOR and p70S6K during early phase of wound healing. Application of rapamycin to monoculture NF and KF, dose- and time-dependently downregulates the expression of cytoplasmic PCNA, cyclin D1, fibronectin, collagen and alpha-SMA, demonstrating the anti-proliferative effect and therapeutic potential of rapamycin in the treatment of keloid scars. The inhibitory effect of rapamycin was found to be reversible following recovery in the expression of proteins following the removal of rapamycin from the culture media. These results demonstrate the important role of mTOR in the regulation of cell cycle and the expression of ECM proteins: fibronectin, collagen and alpha-SMA.
Ong
C T
CT
Department of Surgery, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260.
Khoo
Y T
YT
Mukhopadhyay
A
A
Do
D V
DV
Lim
I J
IJ
Aalami
O
O
Phan
T T
TT
D000199:Actins / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D002648:Child; D017439:Cicatrix, Hypertrophic / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007627:Keloid / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
D000199:Actins; D056741:Cyclin D; D016213:Cyclins; D005353:Fibronectins; D018809:Proliferating Cell Nuclear Antigen; D003094:Collagen; D011494:Protein Kinases; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus