Mitogenic function of human procathepsin D: the role of the propeptide

Abstract

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.

Procathepsin D in breast cancer: What do we know? Effects of ribozymes and other inhibitors

“…Additional experiments showed the presence of saturable, M6P-independent binding sites. 78 The proofs of the new pathway of pCD interaction with cell membrane were further strengthened by the finding that the binding of FITC-labeled pCD to cancer cells can be inhibited by unlabeled procathepsin but only marginally by either M6P, anti -M6P-R antibodies, or by soluble M6P-R. 56,79 In addition, the biological activities of pCD cannot be blocked by anti -M6P-R antibodies.…”

Cathepsin D is partly endocytosed by the LRP1 receptor and inhibits LRP1-regulated intramembrane proteolysis

“…Human cath-D is synthesized as a 52-kDa precursor that is rapidly converted in the endosomes to form an active, 48-kDa, single-chain intermediate, and then in the lysosomes into the fully active mature protease, composed of a 34-kDa heavy chain and a 14-kDa light chain (Gieselmann et al, 1985). The overexpression of cath-D in breast cancer cells leads to the hypersecretion of the 52-kDa pro-cath-D into the extracellular environment (Vignon et al, 1986;Capony et al, 1989;Fusek and Vetvicka, 1994). Cath-D affects both the cancer cells and the stromal cells of the tumor microenvironment.…”

“…Inhibition of cath-D expression in breast cancer cells decreases tumor growth and metastasis Ohri et al, 2007;Vashishta et al, 2007). Human secreted pro-cath-D stimulates breast cancer cell proliferation (Vignon et al, 1986;Fusek and Vetvicka, 1994;Vetvicka et al, 1994;Ohri et al, 2008), fibroblast outgrowth (Laurent-Matha et al, 2005) and angiogenesis (Hu et al, 2008). We have shown that a mutated catalytically inactive version of cath-D (D231N) is still mitogenic for tumor cells and fibroblasts (Glondu et al, 2001;Berchem et al, 2002;Laurent-Matha et al, 2005).…”

Cathepsin D—Many functions of one aspartic protease

“…Since that time, numerous studies clearly demonstrated that pCD secreted from cancer cells serve as an autocrine growth factor for breast [180,181], prostate [182,183], ovarian [184] and lung cancer cells [185,186]. Breast cancer cells with down-regulated expression of pCD by either antisense gene transfer [187], RNA interference [188] or ribozymes [189] displayed reduced growth in vitro and in vivo.…”