Molecular Characteristics of Multicorn, a New Large Proteolytic Assembly and Potential Anti-Cancer Drug Target, in Human Breast Cancer Cells

摘要

Proper regulation of cell division and cell differentiation are the major factors preventing the neoplastic growth. Proteolysis is one of the widely accepted controlling mechanisms of these processes. The proteasome is the best known executor of controlled proteolysis in human cells. We discovered and biochemically characterized the multicorn, a giant proteolytic complex distinct from the proteasome. We found the multicorn to be identical with tripeptidyl peptidase II (TPP II), a ubiquitous eukaryotic protease of obscure functions. We found cell cycle-dependent differences in modifications and subcellular localization of TPP II in human breast cancer MCF-7 cells, as compared with non-cancerous MCF-lOA cells. The total activity of TPP II seems to be several-fold lower in cancerous cells than in control cells. These intriguing observations suggest a likely involvement of TPP II in cell cycle progression, a novel notion about the protease. Most importantly, we observed that cancerous cells are much more vulnerable than control cells to cell death induced by the combined treatment with low doses of inhibitors of the proteasome and TPP II. Our findings confirm that the TPP II, most likely together with the proteasome, can be a useful anti-cancer drug target and a marker of neoplastic transformation.