A strategy to improve selectivity and targeting to epithelial-derived cancer cells

Journal of Controlled Release : Official Journal of the Controlled Release Society
Keyi LiuR J Mrsny

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 ...Continue Reading

References

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