Farnesyltransferase inhibitor SCH‐66336 downregulates secretion of matrix proteinases and inhibits carcinoma cell migration

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Abstract
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 μM 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.

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