Statins are widely used for the treatment of hypercholesterolemia. However, their inhibitory action on HMG-CoA reductase also results in the depletion of intermediate biosynthetic products, which importantly contribute to cell proliferation. The aim of the present study was to compare the effects of the individual commercially available statins on experimental pancreatic cancer. The in vitro effects of individual statins (pravastatin, atorvastatin, simvastatin, lovastatin, cerivastatin, rosuvastatin and fluvastatin) on the viability of human pancreatic cancer were evaluated in CAPAN-2, BxPc-3 and MiaPaCa-2 cell lines. The in vivo experiments were performed on nude mice xenotransplanted with CAPAN-2 cells. The mice received oral treatments either with a placebo, or with the statins mentioned earlier in a daily dose corresponding to a hypocholesterolemic dose in humans. The effect of these statins on the intracellular Ras protein, trafficking in MiaPaCa-2 transfected cells, was also investigated. Substantial differences in the tumor-suppressive effects of all statins were detected in both in vitro and in vivo experiments. While simvastatin exerted the highest tumor-suppressive effects in vitro, rosuvastatin (p 5 0.002), cerivastatin (p 5 0.002) and fluvastatin (p 5 0.009) were the most potent compounds in an animal model. All statins (except pravastatin) inhibited intracellular Ras protein translocation. In summary, substantial tumor-suppressive effects of various statins on the progression of experimental pancreatic adenocarcinoma were demonstrated, with marked differences among individual statins. These results support greatly the potential of statins for the chemoadjuvant treatment of pancreatic cancer. ' 2007 Wiley-Liss, Inc.

Cajal bodies (CBs) are evolutionarily conserved nuclear structures involved in the metabolism of spliceosomal small nuclear ribonucleoprotein particles (snRNPs). CBs are not present in all cell types, and the trigger for their formation is not yet known. Here, we depleted cells of factors required for the final steps of snRNP assembly and assayed for the presence of stalled intermediates in CBs. We show that depletion induces formation of CBs in cells that normally lack these nuclear compartments, suggesting that CB nucleation is triggered by an imbalance in snRNP assembly. Accumulation of stalled intermediates in CBs depends on the di-snRNP assembly factor SART3. SART3 is required for both the induction of CB formation as well as the tethering of incomplete snRNPs to coilin, the CB scaffolding protein. We propose a model wherein SART3 monitors tri-snRNP assembly and sequesters incomplete particles in CBs, thereby allowing cells to maintain a homeostatic balance of mature snRNPs in the nucleoplasm.

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Despite extensive data demonstrating that immature retroviral particle assembly can take place either at the plasma membrane or at a distinct location within the cytoplasm, targeting of viral precursor proteins to either assembly site still remains poorly understood. Biochemical data presented here suggest that Tctex-1, a light chain of the molecular motor dynein, is involved in the intracellular targeting of Mason-Pfizer monkey virus (M-PMV) polyproteins to the cytoplasmic assembly site. Comparison of the three-dimensional structures of M-PMV wild-type matrix protein (wt MA) with a single amino acid mutant (R55F), which redirects assembly from a cytoplasmic site to the plasma membrane, revealed different mutual orientations of their C-and N-terminal domains. This conformational change buries a putative intracellular targeting motif located between both domains in the hydrophobic pocket of the MA molecule, thereby preventing the interaction with cellular transport mechanisms.capsid assembly ͉ dynein motor ͉ matrix protein structure ͉ retrovirus ͉ transport G ag polyproteins are major structural subunits of immature retroviral capsids and contain the determinants that mediate interactions with viral genomic RNA as well as particle assembly. The molecular mechanisms that control the accumulation of Gag molecules at the sites of assembly vary among retroviruses. Based on the assembly site, retroviruses have been shown to follow two major morphogenic pathways (1). While alpharetroviruses, gammaretroviruses, and lentiviruses (C-type retroviruses) assemble immature capsids at the inner side of the plasma membrane, the capsids of betaretroviruses (B/D-type) are formed in the cytoplasm. It has been shown that MasonPfizer monkey virus (M-PMV), which is the prototype of the D-type retroviruses, assembles at the pericentriolar region of an infected cell (2). Numerous studies have demonstrated that the matrix protein (MA), located at the N terminus of the Gag polyprotein, is responsible for targeting the polyprotein precursors to the site of assembly and for mediating transport of immature retroviral particles to the plasma membrane where budding occurs (3). A subtle difference in the regulation of the transport process has been suggested, as the results from several laboratories indicate that the destination of polyprotein precursors can be altered by mutations within MA. Amino acid substitutions in several domains of HIV-1 MA dramatically reduced the efficiency of particle production and redirected the majority of them to cytoplasmic vacuoles (4). Similarly, a substitution of basic for acidic residues in helix A of HIV-1 MA caused relocation of virus assembly to intracellular locations and produced normally budded noninfectious virions (5). Mutation of the N-terminal polybasic region of Moloney murine leukemia virus (Mo-MuLV) MA redirected virus assembly to the cytoplasm, suggesting a role of tryptophan residues in the intracellular transport (6).The N terminus of MA from most retroviruses, including M-PMV, is myristoylat...

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