High levels of transglutaminase expression in doxorubicin-resistant human breast carcinoma cells

Tissue type II transglutaminase (TGase) is a member of the TGase family that catalyzes Ca(2+)-dependent covalent cross-linking of several amines to the gamma-carboxamide group of protein-bound glutamine residues. The degree of therapeutic efficacy or toxicity of drugs may be related to their ability to serve as a substrate for TGase and their covalent linkage to glutamine residues of regulatory proteins through the catalytic action of this enzyme. Here, doxorubicin (adriamycin)-resistant human breast carcinoma MCF-7ADR cells exhibited 40- to 6C-fold higher TGase activity than control drug-sensitive MCF-7WT cells. The same was observed in vivo: a small proportion of tumor cells became positive for TGase after administration of adriamycin-based chemotherapy to patients with breast carcinoma. Similarly, continuous culture of MCF-7WT cells in the presence of adriamycin led to the appearance of the drug-resistant phenotype that was in turn associated with increased expression of TGase. This increase in TGase was specific for adriamycin resistance. Like most known TGase, MCF-7ADR TGase was completely dependent on the presence of Ca2+ for its catalytic activity. Based on its immunoreactivity, the TGase in MCF-7ADR cells was identified...Continue Reading