Derlin-1 is overexpressed on the tumor cell surface and enables antibody-mediated tumor targeting therapy
Y Ran, H Hu, D Hu, Z Zhou, Y Sun, L Yu, L Sun… - Clinical Cancer …, 2008 - AACR
Y Ran, H Hu, D Hu, Z Zhou, Y Sun, L Yu, L Sun, J Pan, J Liu, T Liu, Z Yang
Clinical Cancer Research, 2008•AACRPurpose: 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. Experimental Design: The cell surface …
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. Experimental Design: The cell surface …
Abstract
Purpose: 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.
Experimental Design: 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 125I-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.
Results: 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.
Conclusions: 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.
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