Phosphatase and tensin homologue deleted on chromosome ten (PTEN) as a molecular target in lung epithelial wound repair

JP Lai, JT Dalton, DL Knoell - British journal of pharmacology, 2007 - Wiley Online Library
British journal of pharmacology, 2007Wiley Online Library
Background and purpose: 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. Experimental approach: We
evaluated the ability of two bisperoxovanadium derivatives, bpV (phen) and bpV (pic), in …
Background and purpose
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.
Experimental approach
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.
Key results
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.
Conclusions and implications
From these studies, we conclude that PTEN is a valid target for future studies directed at restoring epithelial barrier function after lung injury.
British Journal of Pharmacology (2007) 152, 1172–1184; doi:10.1038/sj.bjp.0707501; published online 8 October 2007
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