Data from Derlin-1 Is Overexpressed on the Tumor Cell Surface and Enables Antibody-Mediated Tumor Targeting Therapy

Abstract

<div>Abstract<p><b>Purpose:</b> Tumor targeting therapy is one of the most promising strategies for anticancer treatment. Derlin-1 has been reported to participate in misfolded protein dislocation and integrates into the endoplasmic reticulum (ER) membrane to survey for such protein aggregates. We elucidate herein that Derlin-1 can leak to the plasmalemma from the ER in tumor cells and may have clinical application as a novel cancer target in the hope of developing a new tumor targeting therapy.</p><p><b>Experimental Design:</b> The cell surface expression of Derlin-1 was shown by immunofluorescence analysis of nonpermeabilized cells and Western blotting of fractional proteins of tumor cells. Derlin-1 expression in cancerous tissues was also shown by immunohistochemistry. Biodistribution analysis and γ-scintigraphic imaging were done using <sup>125</sup>I-labeled Derlin-1 targeting antibody in isogenic mice models. Finally, tumor-bearing mice were treated by the anti-Derlin-1 polyclonal antibody and monoclonal antibodies.</p><p><b>Results:</b> Derlin-1 was expressed on various tumor cell surfaces and adopted a homodimer conformation. Robust cytoplasmic and membrane expression of Derlin-1 was detected in various types of human cancers tissues but was not correlated with any clinicopathologic features of pancreatic cancer. Derlin-1 directed antibodies specifically targeted to colon tumors and significantly suppress tumor growth in isogenic mice.</p><p><b>Conclusions:</b> These preclinical data show that Derlin-1 protein is a functional molecular target expressed on the tumor cell surface and is a candidate therapeutic target that may be translated into clinical applications.</p></div>