Purpose: Polyisoprenylation is a set of secondary modifications involving proteins whose aberrant activities are implicated in cancers and macular degeneration. This process is essential for the activities of oncogenic proteins such as Ras. The terminal reversible step of polyisoprenylation pathway is catalyzed by an ester forming polyisoprenylated protein methyl transferase and polyisoprenylated methylated protein methyl esterase (PMPMEase). PUFAs share structural similarities with the polyisoprenyl groups and may interfere with polyisoprenylated protein metabolism. Methods: The effect of PUFAs on purified PMPMEase activity was studied. The inhibitory PUFAs were further evaluated on the viability of various cancer cell lines. The PMPMEase activity in the lysates of treated cells was analyzed in the presence or absence of COX-2/celecoxib. The mechanism of PUFAs-induced cell death was determined using a modified ethidium bromide and acridine orange (EB/AO) staining assay. Results: PUFAs such as arachidonic (AA), eicosapentaenoic and docosahexaenoic acids inhibited purified PMPMEase activity with Ki values of 0.12 to 3.7 µM. Enzyme kinetics analysis with PMPMEase revealed a 2- fold decrease in KM from 16.2 ± 1.34 to 8.60 ± 1.20 and 7.84 ± 1.02 μM in the presence of 10 μM AA or EPA, respectively. AA also induced the degeneration of various cancer cells at physiologically relevant concentrations (EC50 from 1 to 24 μM). The cellular PMPMEase activity also followed similar profiles to those of the cell viabilities in concentration-dependent studies. Treated degenerating cells displayed diminished PMPMEase activities. The inhibited PMPMEase activities in PUFAs-treated cells were restored by the addition of COX-2 but not in the presence of celecoxib. Conclusions: These data suggest that AA and other PUFAs, functioning through PMPMEase inhibition, may be involved in the regulation of cell proliferation. NSAIDs may thus owe their anticancer effects by protecting the PMPMEase- and cell proliferation-inhibiting PUFAs from COX-2 metabolism.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3221. doi:1538-7445.AM2012-3221