Mitogenic function of human procathepsin D: the role of the propeptide.
The proform of cathepsin D is secreted by some human breast-cancer cell lines upon stimulation with oestrogen. In these cell lines, procathepsin D was described to act as an autocrine mitogen, and a correlation between the cathepsin D concentration in tumour tissues and poor prognosis for the patient was demonstrated in several independent investigations. In the present study, we focused on the mechanism of procathepsin D mitogenic activity. Procathepsin D isolated from secretions of ZR-75-1 breast-cancer cell line was used to test for mitogenic activity on a set of seven human cell lines. For nanomolar procathepsin D concentrations, we found a stronger dose-responsive cellular reaction in the case of several different human breast-cancer-derived cell lines. The mitogenic activity was not blocked by the inhibition of proteolytic activity nor by the inhibition of the interaction of procathepsin D with mannose-6-phosphate receptors. On the other hand, the addition of antibodies raised against the propeptide impaired the mitogenic activity of procathepsin D, and a synthetic peptide alone corresponding to the propeptide of procathepsin D produced similar effects, as did the zymogen molecule. The synthetic propeptide was shown to block partially the interaction of procathepsin D with the cellular surface. Our results indicate that the mitogenic function involves the propeptide of cathepsin D, which appears to be recognized by a surface receptor.
Oklahoma Medical Research Foundation, Oklahoma City 73104.
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D002402:Cathepsin D / Q000502:physiology*; D002455:Cell Division; D004792:Enzyme Precursors / Q000502:physiology*; D016650:Fluorescein-5-isothiocyanate; D006801:Humans; D006868:Hydrolysis; D007335:Insulin-Like Growth Factor II / Q000502:physiology; D008934:Mitogens / Q000502:physiology*; D010455:Peptides / Q000502:physiology; D014407:Tumor Cells, Cultured
D004792:Enzyme Precursors; D008934:Mitogens; D010455:Peptides; D007335:Insulin-Like Growth Factor II; C058345:procathepsin D; D002402:Cathepsin D; D016650:Fluorescein-5-isothiocyanate