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

Abstract

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. Keywords: PTEN; lung; epithelium; wound remodelling Abbreviations: bpV(phen), potassium bisperoxo (1,10-phenanthroline) oxovanadate; bpV(pic), di-potassium bisperoxo (picolinato) oxovanadate; DN, dominant negative; GSK3, glycogen synthase kinase-3; hUAECs, primary human upper airway epithelial cells; LDH, lactate dehydrogenase; PBS, phosphate-buffered solution; PI(3,4,5)P 3 , phosphatidyl-inositol 3,4,5-trisphosphate; PI3K, phosphoinositide-3 kinase; PTEN, phosphatase and tensin homologue deleted on chromosome ten; WST-1, water-soluble tetrazolium salt

mir‑106a regulates cell proliferation and apoptosis of colon cancer cells through targeting the PTEN/PI3K/AKT signaling pathway

“…And there was a natural inhibitor that named PTEN to inhibit the activation of PI3K/AKT signaling pathway, thus limiting cell proliferation and cancer progression; furthermore, knocking out of PTEN was shown to elevate the mass of brain on account of the corresponding unregulated proliferation (21). Administration of PTEN inhibitor was found to temporarily and safely impact the activation of PI3K/AKT signaling pathway thus influencing cell survival (22) and proliferation (23).…”

Elevated Phosphatidylinositol 3,4,5-Trisphosphate in Glia Triggers Cell-Autonomous Membrane Wrapping and Myelination

“…logic decrease of PTEN activity may be tolerated, and small molecule inhibitors (Rosivatz et al, 2006;Lai et al, 2007) could qualify as drug candidates to trigger remyelination.…”

Formyl Peptide Receptor Ligands Promote Wound Closure in Lung Epithelial Cells

“…After scratch wound generation in Beas2B cells (16) and replacement with fresh media, cells were treated with necrotic HepG2 cells or mitochondrial subfraction proteins, 2% FBS, or the FPR agonist ND6. In some instances, preincubation with FPR inhibitors, cyclosporin H (CsH) (1 mM) or Boc-Phe-Leu-Phe-Leu-Phe (BOC; 10 mM), or an IL-8 blocking antibody (1 mg/ml) (R&D Systems, Minneapolis, MN) were made.…”