Editors' ChoiceCancer

Secreted Cathepsin Stimulates Growth

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Science's STKE  08 Feb 2005:
Vol. 2005, Issue 270, pp. tw57
DOI: 10.1126/stke.2702005tw57

Cathepsin D is a lysosomal aspartyl protease that has also been implicated in breast cancer and metastasis. The tumor progression properties do not require the catalytic activity of the enzyme but do appear to be related to hyperexpression and secretion of the enzyme from cancer cells. Laurent-Matha et al. report that human breast cancer MCF-7 cells promoted the outgrowth of fibroblasts (human skin, human mammary, or mouse fibroblasts deficient for cathepsin D). Rat 3Y1-Ad12 cancer cells engineered to secrete higher-than-normal levels of wild-type or catalytically inactive cathepsin D also stimulated mouse fibroblast outgrowth, whereas rat cancer cells that did not hypersecrete cathepsin D did not. RNA interference was used to inhibit the production of cathepsin D in MCF-7 cells, and these cells were impaired in their ability to stimulate fibroblast outgrowth. Mouse fibroblasts engineered to express wild-type or catalytically inactive human cathepsin D were compared to mouse fibroblasts deficient in cathepsin D, and the cathepsin D-positive cells were more invasive in two assays and exhibited enhanced migration in a wound-healing assay compared to the cathepsin D-deficient cells. Cathepsin D-positive cells also exhibited enhanced proliferation and decreased apoptosis compared to that observed for cathepsin D-deficient cells. Cathepsin D stimulated the extracellular signal-regulated kinase (ERK) pathway, based on increased phosphorylation of ERK in the cathepsin D-positive cells, and pharmacological inhibition of the upstream kinase MEK inhibited the invasive growth phenotype. That it was secreted cathepsin D that was responsible for the invasive growth phenotype and ERK stimulation was verified using conditioned medium from the wild-type or catalytically inactive cathepsin D cells. Thus, secreted cathepsin D appears to have a paracrine role in promoting invasive growth.

V. Laurent-Matha, S. Maruani-Herrmann, C. Prébois, M. Beaujouin, M. Glondu, A. Noël, M. L. Alvarez-Gonzalez, S. Blacher, P. Coopman, S. Baghdiguian, C. Gilles, J. Loncarek, G. Freiss, F. Vignon, E. Liaudet-Coopman, Catalytically inactive human cathepsin D triggers fibroblast invasive growth. J. Cell Biol. 168, 489-499 (2005). [Abstract] [Full Text]

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