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- Title
Phosphatase and tensin homologue deleted on chromosome ten (PTEN) as a molecular target in lung epithelial wound repair.
- Authors
Lai, J.-P.; Dalton, J. T.; Knoell, D. L.
- Abstract
<bold>Background and Purpose: </bold>Epithelial injury contributes to lung pathogenesis. Our work and that of others have identified the phosphoinositide-3 kinase (PI3K)/Akt pathway as a vital component of survival in lung epithelia. Therefore, we hypothesized that pharmacological inhibition of PTEN, a major suppressor of this pathway, would enhance wound closure and restore lung epithelial monolayer integrity following injury.<bold>Experimental Approach: </bold>We evaluated the ability of two bisperoxovanadium derivatives, bpV(phen) and bpV(pic), in differentiated primary human airway epithelia and BEAS2B cultures for their ability to inhibit PTEN, activate the PI3K/Akt pathway and restore epithelial monolayer integrity following mechanical injury.<bold>Key Results: </bold>BpV(phen) and bpV(pic) induced Akt phosphorylation in primary and BEAS2B cells in a dose and time dependent manner. Minimal toxicity was observed as measured by lactate dehydrogenase (LDH) release. To verify that Akt phosphorylation is specifically induced by PTEN inhibition, the PTEN positive cell line, DU145, and two PTEN negative cell lines, LNCaP and PC3, were examined. PTEN positive cells demonstrated a dose responsive increase in Akt phosphorylation whereas PTEN negative cells showed no response indicating that bpV(phen) directly suppresses PTEN without affecting auxiliary pathways. Next, we observed that exposure to either compound resulted in accelerated wound closure following mechanical injury. Similar effects were observed after transfection with a dominant negative isoform of PTEN and PTEN specific siRNA.<bold>Conclusions and Implications: </bold>From these studies, we conclude that PTEN is a valid target for future studies directed at restoring epithelial barrier function after lung injury.
- Subjects
PHOSPHATASES; CHROMOSOMES; LUNGS; EPITHELIAL cells; PHOSPHOINOSITIDES; WOUND healing; DRUG delivery systems; RESEARCH; HETEROCYCLIC compounds; PHOSPHOTRANSFERASES; TIME; RESEARCH methodology; EVALUATION research; MEDICAL cooperation; ORGANOMETALLIC compounds; CELLULAR signal transduction; COMPARATIVE studies; LACTATE dehydrogenase; DOSE-effect relationship in pharmacology; TRANSFERASES; RESEARCH funding; CELL lines; ESTERASES; PHOSPHORYLATION; CHEMICAL inhibitors
- Publication
British Journal of Pharmacology, 2007, Vol 152, Issue 8, p1172
- ISSN
0007-1188
- Publication type
journal article
- DOI
10.1038/sj.bjp.0707501