Accelerated wound healing by mTOR activation in genetically defined mouse models.
BACKGROUND
The management of slow or non-healing ulcerations constitutes an increasing clinical challenge in the developed world because of the ageing of the population and the pandemic rise in type II diabetes. Recent studies suggest that molecular circuitries deployed by tumor cells to promote cancerous growth may also contribute to tissue regeneration. Here, we exploited this emerging information to search for novel molecular targets to accelerate wound healing.


RESULTS
We found that the activation of the PI3K-Akt-mTOR pathway, whose aberrant function is a frequent event in human neoplasia, represents an integral component of the normal wound healing process. By the use of genetically defined approaches, including the epithelial-specific ablation of Pten and Tsc1, we show that mTOR activation can dramatically increase epithelial cell proliferation, migration, and cutaneous wound healing, while pharmacological inhibition of mTOR with rapamycin delays wound closure.


CONCLUSIONS
Overall, our findings indicate that the transient pharmacologic activation of the PI3K-Akt-mTOR signaling axis may represent a novel clinical intervention strategy to accelerate the healing of debilitating and life-threatening wounds.
Squarize
Cristiane H
CH
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, United States of America.
Castilho
Rogerio M
RM
Bugge
Thomas H
TH
Gutkind
J Silvio
JS
D000818:Animals; D002451:Cell Compartmentation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D017353:Gene Deletion; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D015603:Keratinocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051379:Mice; D023421:Models, Animal; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D012867:Skin / Q000187:drug effects / Q000473:pathology; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects
D047908:Intracellular Signaling Peptides and Proteins; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D020123:Sirolimus