期刊
CLINICAL CANCER RESEARCH
卷 14, 期 20, 页码 6538-6545出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-08-0476
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资金
- National Key Basic Research Program of China [2009CB 521804]
- National High-tech RD Program [2006AA 02Z479]
- National Natural Science Foundation of China [30570818, 30600279]
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 tumorcells. Derlin-1 expression in cancerous tissues was also shown by immunohistochemistry. Biodistribution analysis and gamma-scintigraphic imaging were done using I-125-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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