The nuclear DNA repair protein Ku70/80 is a tumor‐associated antigen displaying rapid receptor mediated endocytosis

Abstract

To be of therapeutic relevance, a tumor-associated antigen should be expressed on the surface of neoplastic cells but not, or to a significantly lower extent, on cells of non-transformed nature. The Ku heterodimer (Ku70/80) is involved in DNA double strand break recognition and repair and is ubiquitously expressed in the nucleus of all cells. However, its exclusive nuclear localization has been reassessed by studies that demonstrate Ku to be expressed on the surface of tumor cell lines, displaying functions in cell adhesion, migration and invasion. In this study, we add another feature to the pluripotent role of Ku70/80 by showing that, upon binding the novel human recombinant antibody INCA-X, the Ku70/80 heterodimer is internalized into pancreatic carcinoma cells. The receptor-mediated endocytosis of Ku70/80 is rapid (t 1/2 12 min) and extensive (90% of the receptor pool inside the cell after 100 min) as measured by rotating radioimmunoassay. Ku70/80 was also successfully used as a port of entry for cytotoxic payloads to tumor cells of various origin, as determined by indirect immunotoxin administration of a saporin-conjugated, secondary anti-human antibody. Thus, the internalization properties of the Ku70/80 suggest a potential role of this tumor associated antigen in selective drug-delivery in several human malignancies. ' 2006 Wiley-Liss, Inc.

Ku80 interaction with apurinic/apyrimidinic sites depends on the structure of DNA ends

“…Interestingly, the set of Ku80 peptides identified in this work is almost overlapped with those obtained in the other works [4,10]. This is probably due to an easy ionization of these peptides under the analysis conditions.…”

7B7: a novel antibody directed against the Ku70/Ku80 heterodimer blocks invasion in pancreatic and lung cancer cells

“…A number of antibodies have been developed against Ku70/Ku80; only one of these, the INCA-X antibody, has been demonstrated to show membrane-associated Ku70/Ku80 expression in human cancer tissue, glioma [36]. This group also demonstrated, using their antibody, that Ku70/Ku80 is internalised into pancreatic carcinoma cells, suggesting that it has potential therapeutic value [37]. To our best knowledge, the involvement of Ku70/Ku80 in invasion of this aggressive cancer type or in lung cancer has not been studied to date.…”

β-Carotene-induced apoptosis is mediated with loss of Ku proteins in gastric cancer AGS cells

“…Several studies showed that Ku70/80 has been detected on the plasma membrane of a wide range of different human tumor-derived cell lines such as myeloma, leukemia, and cervix carcinoma (Fransson and Borrebaeck 2006;Muller et al 2005). Ku70/80 levels in the cell surface of the transformed cells are involved in adhesion, migration, and invasion (Muller et al 2005;Tai et al 2002).…”