Release of cytokeratin-18 and -19 fragments (TPS and CYFRA 21-1) into the extracellular space during apoptosis

• Published in: Journal of cellular biochemistry Vol. 85; no. 4; pp. 670 - 677
• Main Authors: Sheard, Michael A., Vojtesek, Borek, Simickova, Marta, Valik, Dalibor
• Format: Journal Article
• Language: English
• Published: New York Wiley Subscription Services, Inc., A Wiley Company 2002
• Subjects: Antigens, Neoplasm - metabolism; Apoptosis - physiology; Biomarkers, Tumor - secretion; breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Breast Neoplasms - secretion; caspase; Caspases - metabolism; CD95/Fas; Extracellular Space - metabolism; Female; Humans; Keratin-19; Keratins - secretion; Peptide Fragments - secretion; Peptides - secretion; proliferation; Solubility; Tumor Cells, Cultured; tumor marker
• ISSN: 0730-2312; 1097-4644
• DOI: 10.1002/jcb.10173

Serum fragments of cytokeratins‐18 and ‐19 (measured as TPS and CYFRA 21‐1, respectively) have traditionally been considered as markers of tumor proliferation, although the evidence is scarce for a causative relationship between proliferation and levels of TPS and CYFRA 21‐1. We examined whether apoptosis might produce TPS and CYFRA 21‐1 fragments. MCF‐7 breast cancer cells were treated with mitomycin C or agonistic anti‐CD95 antibody, and levels of TPS and CYFRA 21‐1 in tissue culture supernatants were compared with the frequency of cells exhibiting the following markers of cell death: intracellular cytokeratin‐18 cleavage, surface staining with annexin‐V, propidium iodide uptake, DNA fragmentation. Twenty‐four hours after inducing apoptosis, levels of TPS and CYFRA 21‐1 were elevated ≥ 4‐fold in culture supernatants. Elevations in TPS and CYFRA 21‐1 coincided with apoptosis measured by the first three cell death markers but preceded DNA fragmentation. These mitomycin C‐ and CD95‐mediated elevations were completely inhibited by co‐incubation with the caspase inhibitors Z‐VAD.fmk and Z‐IETD.fmk, respectively. We conclude that TPS and CYFRA 21‐1 can be abundantly released into the extracellular space during the intermediate stage of epithelial cell apoptosis. J. Cell. Biochem. 85: 670–677, 2002. © 2002 Wiley‐Liss, Inc.