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Gucy2c Lysosomotropic Endocytosis Delivers Immunotoxin Therapy To Metastatic Colorectal Cancer., Glen P Marszalowicz, Adam E. Snook, Michael Sullivan Magee, Dante Merlino, Lisa D Berman-Booty, Scott A Waldman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

The emergence of targeted cancer therapy has been limited by the paucity of determinants which are tumor-specific and generally associated with disease, and have cell dynamics which effectively deploy cytotoxic payloads. Guanylyl cyclase C (GUCY2C) may be ideal for targeting because it is normally expressed only in insulated barrier compartments, including intestine and brain, but over-expressed by systemic metastatic colorectal tumors. Here, we reveal that GUCY2C rapidly internalizes from the cell surface to lysosomes in intestinal and colorectal cancer cells. Endocytosis is independent of ligand binding and receptor activation, and is mediated by clathrin. This mechanism suggests a design for …