Farnesyltransferase inhibitors inhibit T-cell cytokine production at the posttranscriptional level

Abstract

IntroductionSmall GTPases of the Ras family such as Ras, Rho, and Rac are important regulators of growth factor receptor-induced activation events in a variety of cellular systems. A hallmark of GTPases like N-, K-, and H-Ras is that several posttranslational modifications of the synthesized protein must occur before localization to distinct cell membranes is achieved, a necessary prerequisite for functional activity. 1 Prenylation catalyzed by 1 of 3 intracellular enzymes, farnesyltransferase (FTase) or geranylgeranyltransferases (GGTase I and II), is the first critical modification step. Physiologically, prenylation in posttranslational processing of Ras proteins in mammalian cells is predominantly achieved by FTase. However, in cells where FTase activity is blocked, alternative prenylation of K-Ras, N-Ras, and RhoB by GGTase I has been described. 2 The FTase substrate in all Ras family proteins is the common COOHterminal CAAX tetrapeptide sequence. FTase catalyzes the transfer of a 15-carbon farnesyl group from farnesyldiphosphate, a product of the cholesterol biosynthesis pathway, to the CAAX cysteine residue. 3 Besides members of the Ras family and a variety of additional molecules such as HDJ-2 and Lamin A and B, several retinal and centromere-associated proteins are also known substrates of cellular FTase. [4][5][6] Further posttranslational modification for membrane targeting of Ras proteins after prenylation includes proteolysis of the AAX motif followed by alpha-carboxymethylation of the farnesylated cysteine residue. In addition, H-Ras and N-Ras are subsequently palmitoylated. 7 Since posttranslational isoprenoid modification is regarded as the critical event in localization of Ras proteins to cellular membranes, preventing the synthesis of the farnesyl precursor mevalonate by blocking of HMG-CoA reductase results in the depletion of intracellular farnesyl and accumulation of nonprocessed cytosolic Ras. 8 Furthermore, statins, which are HMG-CoAinhibitors widely used as cholesterollowering agents, have recently been attributed clinically relevant immunomodulatory properties. 9 Farnesyltransferase inhibitors (FTIs) are a class of drugs initially generated to interfere with the farnesylation of oncogenic Ras, thereby retaining it in the cytosol and preventing its activity. The development of several structurally different FTIs as anticancer agents was based on the initial observation that the phenotype of oncogenic Ras-transformed fibroblasts could be reversed by FTI treatment 10 followed by a variety of data regarding the antineoplastic activity of FTIs in several in vitro and in vivo tumor models. 5 Cancer cell lines treated with FTI show inhibition of proliferation, 11 induction of apoptosis, 12 or disturbed cell-cycle progression 13 in vitro. In particular, pediatric T-cell acute lymphoblastic leukemia (ALL) and French-American-British (FAB) M5 acute myeloid leukemia (AML) have been proven very sensitive to FTI-mediated cytotoxicity. 14 Inhibition of malignant cell growth could also be demonstrated ...

N‐Ras or K‐Ras inhibition increases the number and enhances the function of Foxp3 regulatory T cells

“…In line with those observations are reported findings that inhibition of Ras activation results in the development of anti-inflammatory responses [15] and attenuation of experimental autoimmune disorders [14,18,19].…”

“…Those data come from studies showing that mutations in distinct forms of Ras result, both in experimental animals and in humans, in a robust proliferative autoimmune phenotype [13]. In addition, recent data indicate that Ras inhibitors are capable of suppressing experimental autoimmune disorders in animals and favor a T helper (Th)1-dominated phenotype in lymphocytes [14,15].…”

Inhibition of protein geranylgeranylation and farnesylation protects against graft-versus-host disease via effects on CD4 effector T cells

“…Our observation that FTI reduced alloantigen-driven CD4 T-cell proliferation in vitro are, therefore, novel. Furthermore, we extended previous findings 29 by studying the in vivo effects of FTI and GGTI in a GvHD model. Thus the effects of an FTI and a GGTI on alloreactive immune responses that we GvHD protection by FTI and GGTI haematologica | 2013; 98(1) observed are beyond the previously reported in vitro findings using cell lines.…”

“…In vitro studies using murine Th1 and Th2 clones, stimulated in the presence of FTI, showed a dose-dependent reduction of lineage-specific cytokine secretion. 29 The cytokines analyzed in this study included IFN-γ, IL-2, IL-4 and IL-5.…”

“…haematologica | 2013; 98(1) However, the cells used in these studies 29 were clonal cell lines committed to a Th1 or Th2 cytokine profile. Conversely, in our in vitro experiments we used primary T cells which were stimulated by either allogeneic antigenpresenting cells or CD3/CD28 beads.…”