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

Abstract

Purpose: Tumor targeting therapy is one of the most promising strategies for anticancer treatment. Derlin-1has 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-1can 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 andWestern blotting of fractional proteins of tumor cells. Derlin-1expression in cancerous tissues was also shown by immunohistochemistry. Biodistribution analysis and g-scintigraphic imaging were done using 125 I-labeled Derlin-1targeting antibody in isogenic mice models. Finally, tumor-bearing mice were treated by the anti-Derlin-1polyclonal 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-1was 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.

Overexpression of TCL1 activates the endoplasmic reticulum stress response: a novel mechanism of leukemic progression in mice

“…12 Although there is no precedent study on the expression of Derlin proteins in CLL cells ( Figure 2B,D), Derlin-1 is overexpressed in many solid malignancies and is a potential molecular target for therapeutic intervention. 37 Our results now suggest that the IRE-1/ XBP-1 pathway is a promising target for CLL treatment ( TCL1 drives malignant progression of CLL via dysregulated expression of transcription factors and AID ( Figure 3B). IRF4 alone can transform cells in vitro.…”

MiR-598 Suppresses Invasion and Migration by Negative Regulation of Derlin-1 and Epithelial-Mesenchymal Transition in Non-Small Cell Lung Cancer

“…We identified DERL1 as a direct downstream target gene of miR-598 using bioinformatics method that was further confirmed by the luciferase reporter assay. DERL1 is overexpressed in NSCLC; it also promotes cancer cell invasion via EGFR-ERK-mediated upregulation of MMP-2 and MMP-9 [16, 19, 21]. However, the correlation between DERL1 and miR-598 remains unclear.…”

“…The family of Der1 proteins has emerged as a vital component of the ERAD pathway [15]. DERL1 is a partner of the p97 ATPase complex and plays a key role in the mislocalization of the misfolded protein; it also integrates into the endoplasmic reticulum (ER) membrane to survey such protein aggregates [16, 17]. Recently, several studies have demonstrated that DERL1 contributes to carcinogenesis and tumor progression, and the upregulation of DERL1 expression promotes the development of colon cancer, esophageal cancer, and bladder cancer [18-20].…”

Derlin-1 is overexpressed in human colon cancer and promotes cancer cell proliferation

“…Derlin-1, a partner of the p97 ATPase complex, was initially reported to mediate the elimination of misfolded proteins from the endoplasmic reticulum (ER) and retrotranslocation of proteins into the cytosol [3][4][5]. Accumulating evidence has strongly implicated that Derlin-1 plays an important and multifaceted role in cancer progression [6][7][8][9][10][11][12]. Derlin-1 was confirmed to promote hepatocellular carcinoma endothelial cell survival and growth [13].…”