Decreased activity of cathepsins L + B and decreased invasive ability of PC3 prostate cancer cells.
Cancer metastasis involves multiple factors, one of which is the production and secretion of matrix degrading proteases by the cancer cells. Many metastasizing cancer cells secrete the lysosomal proteases, cathepsins L and B, which implicates them in the metastatic process. Cathepsins L and B are regulated by endogenous cysteine proteinase inhibitors (CPI) known as cystatins. An imbalance between cathepsin L and/or B and cystatin expression/activity may be a characteristic of the metastatic phenotype. To determine whether cystatins can attenuate the invasive ability of PC3 prostate cancer cells, cells were transfected with a cDNA coding for chicken cystatin. Expression of chicken cystatin mRNA was determined by PCR analysis. Total cysteine proteinase inhibitory activity, cathepsins L + B activity, and invasion through a Matrigel matrix were assessed. Stably transfected cells expressed the chicken cystatin mRNA and exhibited a significant decrease in secreted cathepsin L + B activity and a small increase in secreted cysteine proteinase inhibitor activity. The ability of cystatin transfected cells to invade the reconstituted basement membrane, Matrigel, was attenuated compared to nontransfected cells or cells transfected with vector alone. We have demonstrated that the cysteine proteinases cathepsins L and B participate in the invasive ability of the PC3 prostate cancer cell line, and we discuss here the potential of using cysteine proteinase inhibitors such as the cystatins as anti-metastatic agents.
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Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Health Sciences Center, Louisville, KY 40292, USA. r0cole01@gwise.louisville.edu
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D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D003094:Collagen; D015891:Cystatins / Q000235:genetics / Q000378:metabolism*; D003546:Cysteine Endopeptidases; D004338:Drug Combinations; D006801:Humans; D007797:Laminin; D008297:Male; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011509:Proteoglycans; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
D015891:Cystatins; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D011994:Recombinant Proteins; C059485:matrigel; D003094:Collagen; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L