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

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 M 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.

Increased mechanosensitivity and nuclear stiffness in Hutchinson–Gilford progeria cells: effects of farnesyltransferase inhibitors

“…Our experiments on cells lacking lamin A strongly suggest that some of the beneficial effects of FTI treatment are caused by targeting farnesylated proteins other than lamin A/progerin. Previous reports demonstrate an inhibitory effect of FTI on cell proliferation and migration at high doses (Kouchi et al, 1999;Kusama et al, 2003Kusama et al, , 2006Desrosiers et al, 2005). Our data, using lower doses of FTI, support the inhibitory effect of FTI on proliferation.…”

The Effect of Ras Inhibition on the Proliferation, Apoptosis and Matrix Metalloproteases Activity in Rat Hepatic Stellate Cells

“…MMPs, such as MMP-2 and MMP-9, display strong activity in tumor cells transformed by Ras [27][28][29]. Contrary to our results, inhibition of Ras by a farnesyltransferase inhibitor reduced levels of secreted MMP-2 and MMP-9 in prostate cancer cells [30]. We observed that FTS together with PDGF and TGFb induced processing of MMP-2 to an active form of approximately 43 kDa.…”

RNA Interference-directed Knockdown of Urokinase Plasminogen Activator and Urokinase Plasminogen Activator Receptor Inhibits Prostate Cancer Cell Invasion, Survival, and Tumorigenicity in Vivo

“…Currently, metastatic prostate cancer is incurable and ultimately claims the life of patients (6 -10). An important factor in the relative seriousness of prostate cancer is the invasiveness of the constituent tumor cells causing metastasis (7,11,12). The invasive nature of tumor cells is crucial for cancer metastasis (13,14).…”