Alendronate blocks TGF-beta1 stimulated collagen 1 degradation by human prostate PC-3 ML cells.
We have previously shown that alendronate can prevent human PC-3 ML tumor cell metastasis to the bone (Wang and Stearns, 1991, Differentiation, 48, 115-25). In this paper, ELISAs and Western blots showed that TGF-beta1 stimulated the secretion of a 72 kDa matrix metalloproteinase 2 (MMP-2) to enhance the solubilization of radiolabeled collagen 1 by metastatic human prostate PC-3 ML cells. A potent bisphosphonate compound, alendronate, inhibited MMP-2 secretion to block solubilization of collagen 1. Alendronate failed to inhibit MMP-2 activity directly, but instead appeared to block cellular secretion of MMP-2. Alendronate failed to inhibit secretion of tissue inhibitor of metalloproteinase-2 (TIMP-2; the inhibitor of MMP-2) and the decrease in collagen 1 solubilization observed may occur, in part, from changes in the molar stoichiometry of TIMP-2 to MMP-2. We conclude that alendronate may be a potent inhibitor of bone resorption based on its ability to block MMP-2 secretion by tumor cells.
Stearns
M E
ME
Allegheny University of the Health Sciences, Department of Pathology, Philadelphia, PA 19102-1192, USA. stearnsm@wpo.auhs.edu
D019386:Alendronate / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001859:Bone Neoplasms / Q000201:enzymology / Q000517:prevention & control / Q000556:secondary; D003094:Collagen / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018093:Gelatinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014316:Tritium; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D016212:Transforming Growth Factor beta; D014316:Tritium; D003094:Collagen; D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D006909:Hydroxyproline; D019386:Alendronate