title: A strategy to improve selectivity and targeting to epithelial-derived cancer cells.
abstract: Examination of genomic and proteomic changes associated with ras-driven epithelial to mesenchymal transformation (EMT) of polarized epithelial cells has led to an improved understanding of surface-expressed structures and alterations in components involved in intracellular trafficking events that are altered as normal cells become cancerous. We have previously identified a mechanism involved in the establishment of tight junction (TJ) cell-cell contacts orchestrated by the protein occludin (Ocln) and its ability to reverse EMT events. Previous studies have suggested an increased functional expression of a cell-surface import system for small peptides, hPepT1, in several types of cancer cells. We now describe two approaches to identify agents capable of re-activating Ocln expression which could be modified into selective substrates of hPepT1. A screen for agents to re-activate suppressed occludin gene (OCLN) expression resulting from Ras/Raf/MEK/ERK pathway activation led to the identification of several small molecules. Using phage panning we have also identified several short peptide sequences that bind to the E-box used by the suppressor protein Slug to block OCLN expression. Thus, the current studies have identified several molecules and a roadmap to generate additional agents that could be examined for their ability to selectively enter cancer cells via hPepT1. We believe this strategy could result in reduced off-target drug distribution and thus greater functional targeting could be achieved for epithelial-derived cancers to prime them for the actions of established chemotherapeutic agents.
authors.affiliation: Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.
authors.forename: Keyi
authors.initials: K
authors.lastname: Liu
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hearne
authors.forename: Adrienne
authors.initials: A
authors.lastname: Mrsny
authors.forename: Cindy
authors.initials: C
authors.lastname: Staka
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Mrsny
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D020935:MAP Kinase Signaling System; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D062793:Occludin / Q000235:genetics* / Q000378:metabolism; D000074011:Peptide Transporter 1; D051381:Rats; D027981:Symporters / Q000378:metabolism
chemical_list: C568985:OCLN protein, human; D062793:Occludin; D000074011:Peptide Transporter 1; C082186:SLC15A1 protein, human; D027981:Symporters