Farnesyltransferase inhibitor SCH-66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration.
The ras oncogenes are among those most frequently found in human cancers. Blocking Ras farnesylation is a promising strategy for arresting cancer growth. Ras activates several signaling pathways with key roles in cellular proliferation, invasion, metastasis and angiogenesis. Furthermore, proteolytic activities of matrix proteinases such as urokinase-type plasminogen activator (uPA) and matrix metalloproteinases (MMPs) are regulated by Ras isoforms. Thus, we investigated the effects of SCH-66336, a farnesyltransferase inhibitor, on secretion of components of the plasminogen activation system as well as on the gelatinases MMP-2 and MMP-9, which play pivotal roles in matrix remodeling. SCH-66336 up to 5 microM did not significantly alter the viability of prostate (PC-3) and renal (Caki-1) cancer cells incubated in serum-depleted medium. SCH-66336 partly inhibited the processing of H-Ras, while levels of mature N-Ras and K-Ras remained unaffected. Under these noncytotoxic conditions, uPA and tPA levels were lowered in culture medium but raised in cell lysates, suggesting inhibition of trafficking pathways. In contrast, SCH-66336 had no effect on uPAR expression or on secreted PAI-1 levels. As expected, the reduction of uPA and tPA activities by SCH-66336 inhibited the conversion of plasminogen to plasmin by about 25% in PC-3 cells. SCH-66336 also inhibited the levels of secreted pro-MMP-2 and pro-MMP-9 as well as the release of their inhibitors TIMP-1 and TIMP-2. SCH-66336 decreased both the adhesion and even more so the migration of PC-3 cells on gelatin. Thus, SCH-66336 inhibited farnesylation in both cancer cell types, and H-Ras functions should be reduced by the drug. In addition, the lower levels of secreted proteinases in the presence of SCH-66336 suggest that reduced matrix remodeling and cell migration should occur in treated tumors.
Desrosiers
Richard R
RR
Laboratoire de médecine moléculaire, Hôpital Sainte-Justine, Université du Québec à Montréal, Montréal, Québec, Canada.
Cusson
Marie-Hélène
MH
Turcotte
Sandra
S
Béliveau
Richard
R
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D002277:Carcinoma / Q000201:enzymology*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D003470:Culture Media / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D005341:Fibrinolysin / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015151:Immunoblotting; D007700:Kinetics; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D020782:Matrix Metalloproteinases / Q000096:biosynthesis*; D010880:Piperidines / Q000494:pharmacology*; D010958:Plasminogen / Q000378:metabolism; D020033:Protein Isoforms; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D003986:Dibenzocycloheptenes
D019883:Alkyl and Aryl Transferases; D003470:Culture Media; D004791:Enzyme Inhibitors; D051231:Farnesyltranstransferase; D005341:Fibrinolysin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D020782:Matrix Metalloproteinases; D010880:Piperidines; D010958:Plasminogen; D020033:Protein Isoforms; D016283:Proto-Oncogene Proteins p21(ras); D011725:Pyridines; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; C524898:PLAUR protein, human; C501009:HRAS protein, human; C115354:lonafarnib; D003986:Dibenzocycloheptenes