Abstract
Small molecule inhibitors of protein geranylgeranyltransferase-I (GGTase-I) provide a promising type of anticancer drugs. Here, we first report the identification of a novel tetrahydropyridine scaffold compound, P61-E7, and define effects of this compound on pancreatic cancer cells. P61-E7 was identified from a library of allenoate-derived compounds made through phosphine-catalyzed annulation reactions. P61-E7 inhibits protein geranylgeranylation and blocks membrane association of geranylgeranylated proteins. P61-E7 is effective at inhibiting both cell proliferation and cell cycle progression, and it induces high p21CIP1/WAF1 level in human cancer cells. P61-E7 also increases p27Kip1 protein level and inhibits phosphorylation of p27Kip1 on Thr187. We also report that P61-E7 treatment of Panc-1 cells causes cell rounding, disrupts actin cytoskeleton organization, abolishes focal adhesion assembly and inhibits anchorage independent growth. Because the cellular effects observed pointed to the involvement of RhoA, a geranylgeranylated small GTPase protein shown to influence a number of cellular processes including actin stress fiber organization, cell adhesion and cell proliferation, we have evaluated the significance of the inhibition of RhoA geranylgeranylation on the cellular effects of inhibitors of GGTase-I (GGTIs). Stable expression of farnesylated RhoA mutant (RhoA-F) results in partial resistance to the anti-proliferative effect of P61-E7 and prevents induction of p21CIP1/WAF1 and p27Kip1 by P61-E7 in Panc-1 cells. Moreover, stable expression of RhoA-F rescues Panc-1 cells from cell rounding and inhibition of focal adhesion formation caused by P61-E7. Taken together, these findings suggest that P61-E7 is a promising GGTI compound and that RhoA is an important target of P61-E7 in Panc-1 pancreatic cancer cells.
Highlights
Proteins such as the Rho family G-proteins are posttranslationally modified by the addition of a geranylgeranyl isoprenoid [1]
From a series of modified compounds, we identified P61-E7 that was synthesized by coupling carboxylic acid of P3-E5 with L-leucine methyl ester to yield an amido ester P61-E7 (Figure 1B)
P61-E7 exhibits increased potency to inhibit protein geranylgeranylation compared to our previous preclinical compound P61-A6 [12,20]
Summary
Proteins such as the Rho family G-proteins are posttranslationally modified by the addition of a geranylgeranyl isoprenoid [1]. The isoprenoid modification is important for membrane association and functions of these proteins. Recent studies have highlighted the significance of protein geranylgeranylation in human cancers. It has been shown that a number of geranylgeranylated proteins play important roles in tumorigenesis and metastasis [2,3,4,5,6]. Conditional knockout of the b-subunit of GGTase-I results in the inhibition of lung tumor growth and increased survival of mice expressing oncogenic K-ras [7]. Inhibition of protein geranylgeranylation is a promising approach for developing anticancer drugs, and inhibitors of GGTase-I (GGTIs) are currently undergoing preclinical studies. The results obtained are consistent with the idea that GGTIs disrupt oncogenic and tumor survival pathways, inhibit proliferation and anchorage-independent growth, and induce apoptosis [8,9,10,11,12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
