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

J Cell Biochem. 2002;85(4):670-7. 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 > or = 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm / metabolism*
  • Apoptosis / physiology*
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Caspases / metabolism
  • Extracellular Space / metabolism
  • Female
  • Humans
  • Keratin-19
  • Keratins / metabolism*
  • Peptide Fragments / metabolism*
  • Peptides / metabolism*
  • Solubility
  • Tumor Cells, Cultured


  • Antigens, Neoplasm
  • Biomarkers, Tumor
  • Keratin-19
  • Peptide Fragments
  • Peptides
  • antigen CYFRA21.1
  • tissue polypeptide specific antigen
  • Keratins
  • Caspases