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Title: Intracellular distribution of TM4SF1 and internalization of TM4SF1-antibody complex in vascular endothelial cells

Transmembrane-4 L-six family member-1 (TM4SF1) is a small plasma membrane-associated glycoprotein that is highly and selectively expressed on the plasma membranes of tumor cells, cultured endothelial cells, and, in vivo, on tumor-associated endothelium. Immunofluorescence microscopy also demonstrated TM4SF1 in cytoplasm and, tentatively, within nuclei. With monoclonal antibody 8G4, and the finer resolution afforded by immuno-nanogold transmission electron microscopy, we now demonstrate TM4SF1 in uncoated cytoplasmic vesicles, nuclear pores and nucleoplasm. Because of its prominent surface location on tumor cells and tumor-associated endothelium, TM4SF1 has potential as a dual therapeutic target using an antibody drug conjugate (ADC) approach. For ADC to be successful, antibodies reacting with cell surface antigens must be internalized for delivery of associated toxins to intracellular targets. We now report that 8G4 is efficiently taken up into cultured endothelial cells by uncoated vesicles in a dynamin-dependent, clathrin-independent manner. It is then transported along microtubules through the cytoplasm and passes through nuclear pores into the nucleus. These findings validate TM4SF1 as an attractive candidate for cancer therapy with antibody-bound toxins that have the capacity to react with either cytoplasmic or nuclear targets in tumor cells or tumor-associated vascular endothelium. - Highlights: • Anti-TM4SF1 antibody 8G4 was efficiently taken up bymore » cultured endothelial cells. • TM4SF1–8G4 internalization is dynamin-dependent but clathrin-independent. • TM4SF1–8G4 complexes internalize along microtubules to reach the perinuclear region. • Internalized TM4SF1–8G4 complexes pass through nuclear pores into the nucleus. • TM4SF1 is an attractive candidate for ADC cancer therapy.« less
Authors:
; ;  [1] ;  [2] ;  [3] ; ;  [1] ;  [1] ;  [1]
  1. Center for Vascular Biology Research and Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School (United States)
  2. Department of Molecular and Cellular Biology, Harvard University (United States)
  3. Department of Pharmacology, Shanxi Medical University, Xinjiannanlu 56, Shanxi Province, Taiyuan 030001 (China)
Publication Date:
OSTI Identifier:
22458554
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 465; Journal Issue: 3; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CYTOPLASM; DELIVERY; DISTRIBUTION; DRUGS; ENDOTHELIUM; GLYCOPROTEINS; IN VIVO; MEMBRANES; MICROTUBULES; MONOCLONAL ANTIBODIES; NEOPLASMS; RESOLUTION; THERAPY; TOXINS; TRANSMISSION ELECTRON MICROSCOPY; TUMOR CELLS