Inhibition of EP2/EP4 signaling abrogates IGF-1R-mediated cancer cell growth : Involvement of protein kinase C-θ activation

Associations between growth factor receptor-mediated cell signaling and cancer cell growth have been previously characterized. Receptors for prostaglandin E2, such as EP2, and EP4, play roles in cancer growth, progression and invasion. Thus, we examined the interactions between EP2/EP4- and IGF-1R-mediated cellular signaling in human pancreatic cancer cells. Selective antagonists against EP2 and EP4 abrogated IGF-1-stimulated cell growth and suppressed MEK/ERK phosphorylation. In subsequent experiments, phospho-antibody arrays indicated increased phosphorylation levels of protein kinase C-θ (PKC-θ) at the Thr538 position following the inhibition of EP2/EP4-mediated signaling. Inhibition of PKC-θ activity impaired cell viability compared with EP2/EP4-antagonized IGF-1-stimulated cells. PKC-θ kinase MAP4K3, which plays a pivotal role in PKC-θ activation, also affected growth signaling in the presence of EP2/EP4 antagonists. Administration of EP2 and EP4 antagonists significantly inhibited the growth of an orthotopic xenograft of IGF-1-secreting pancreatic cancer cells, with increased phospho-PKC-θ and decreased phospho-ERK. Clinico-pathological analyses showed that 17.4% of surgical pancreatic cancer specimens were quadruple-positive for IGF-1R, EP2 (or EP4), MAP4K3, and PKC-θ. These results indicate a novel signaling crosstalk between EP2/EP4 and IGF-1R in cancer cells, and suggest that the MAP4K3-PKC-θ axis is central and could be exploited as a molecular target for cancer therapy

Tsumura-Suzuki obese diabetic mice-derived hepatic tumors closely resemble human hepatocellular carcinomas in metabolism-related genes expression and bile acid accumulation

Background and aims Tsumura-Suzuki obese diabetic (TSOD) is a good model of metabolic syndrome showing typical lesions found in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, and develops spontaneous hepatic tumors with a high frequency. Majority of the developing tumors overexpress glutamine synthetase (GS), which is used as a marker of hepatocellular carcinoma (HCC). The aim of this study is to assess the status of expression of metabolism-related genes and the level of bile acids in the TSOD mice-derived tumors and to determine the association with metabolic dysregulation between human HCC and TSOD mice-derived tumors. Methods GS-positive hepatic tumors or adjacent normal tissues from 71-week-old male TSOD mice were subjected to immunohistochemical staining (IHC), quantitative RT-PCR (qRT-PCR), quantitation of cholic acid and taurocolic acid. Results We found that downregulation of the rate-limiting enzyme for betaine synthesis (BADH), at both mRNA and protein levels in GS-positive TSOD mice-derived tumors. Furthermore, the bile acid receptor FXR and the bile acid excretion pump BSEP (Abcb11) were found to be downregulated, whereas BAAT and Akr1c14, involved in primary bile acid synthesis and bile acid conjugation, were found to be upregulated at mRNA level in GS-positive TSOD mice-derived tumors. BAAT and Akr1c14 was also overexpressed at protein levels. Total cholic acid was found to be increased in GS-positive TSOD mice-derived tumors. Conclusion Our results strongly support the significance of TSOD mice as a model of spontaneously developing HCC

EFFECTS OF COFFEE INTAKE ON METABOLIC SYNDROME

Background: Metabolic syndrome is one of the most important health issues worldwide. Obesity causes insulin resistance, hyperlipidemia, diabetes, and various diseases throughout the body. The liver phenotype, which is called nonalcoholic steatohepatitis (NASH), frequently progresses to hepatocellular carcinoma. We recently established a new animal model, Tsumura-Suzuki obese diabetic (TSOD) mice, which spontaneously exhibit obesity, diabetes, hyperlipidemia, and NASH with liver nodules. Methods: We examined the effects of coffee intake on various conditions of the metabolic syndrome using TSOD mice. The daily volume of coffee administered was limited so that it reflected the appropriate quantities consumed in humans. To clarify the effects of the specific components, animals were divided into two coffee-intake groups that included with and without caffeine. Results: Coffee intake did not significantly affect obesity and hyperlipidemia in TSOD mice. In contrast, coffee intake caused various degrees of improvement in the pancreatic beta cell damage and steatohepatitis with liver carcinogenesis. Most of the effects were believed to be caused by a synergistic effect of caffeine with other components such as polyphenols. However, the antifibrotic effects of coffee appeared to be due to the polyphenols rather than the caffeine. Conclusions: A daily habit of drinking coffee could possibly play a role in the prevention of metabolic syndrome

Theory of Current-Induced Breakdown of the Quantum Hall Effect

By studying the quantum Hall effect of stationary states with high values of injected current using a von Neumann lattice representation, we found that broadening of extended state bands due to a Hall electric field occurs and causes the breakdown of the quantum Hall effect. The Hall conductance agrees with a topological invariant that is quantized exactly below a critical field and is not quantized above a critical field. The critical field is proportional to $B^{3/2}$ and is enhanced substantially if the extended states occupy a small fraction of the system.Comment: 5 pages, RevTeX, final version to appear in PR

Low susceptibility to N-ethyl-N-nitrosourea-induced transplacental carcinogenesis in Long-Evans Cinnamon (LEC) rats

The Long-Evans Cinnamon (LEC) rat, an animal model of Wilson’s disease, is resistant to a variety of chemical carcinogenesis except liver and colon. In the present study, N-ethyl-N-nitrosourea (ENU)-induced transplacental carcinogenesis was examined in male and female LEC, Long-Evans Agouti (LEA), a sibling line of the LEC rat, and F344 rats (n=21). ENU was administered to pregnant rats as a single s.c. injection at a dose of 60 mg/kg body weight on the 17th day after conception. Cerebral/spinal gliomas and trigeminal/spinal nerve schwannomas developed in both LEA and F344 rats at 30 weeks of age, but no nervous system tumors developed in LEC rats, the difference being statistically significant. Lung adenomas also developed in LEA and F344 rats, but not in LEC rats. Semiquantitative RT-PCR demonstrated that metallothionein (MT)1a, MT2 and O6-methylguanine-DNA methyltransferase (MGMT) mRNA levels in the liver of LEC rats were higher than those in F344 and LEA rats. In addition, Western blot analysis showed that MT (MT1 plus MT2) in the liver of LEC rats was also higher than that in other strains. Present results suggest that high levels of MT and/or MGMT contribute to the resistance to nitrosamine-induced carcinogenesis in LEC rats

SV40 miR-S1 and Cellular miR-1266 Sequester Each Other from Their Targets, Enhancing Telomerase Activity and Viral Replication

Virus-encoded microRNAs (miRNAs) target viral and host mRNAs to repress protein production from viral and host genes, and regulate viral persistence, cell transformation, and evasion of the immune system. The present study demonstrated that simian virus 40 (SV40)-encoded miRNA miR-S1 targets a cellular miRNA miR-1266 to derepress their respective target proteins, namely, T antigens (Tags) and telomerase reverse transcriptase (TERT). An in silico search for cellular miRNAs to interact with viral miR-S1 yielded nine potential miRNAs, five of which, including miR-1266, were found to interact with miR-S1 in dual-luciferase tests employing reporter plasmids containing the miRNA sequences with miR-S1. Intracellular bindings of miR-1266 to miR-S1 were also verified by the pull-down assay. These miRNAs were recruited into the Ago2-associated RNA-induced silencing complex. Intracellular coexpression of miR-S1 with miR-1266 abrogated the downregulation of TERT and decrease in telomerase activity induced by miR-1266. These effects of miR-S1 were also observed in miR-1266-expressing A549 cells infected with SV40. Moreover, the infected cells contained more Tag, replicated more viral DNA, and released more viral particles than control A549 cells infected with SV40, indicating that miR-S1-induced Tag downregulation was antagonized by miR-1266. Collectively, the present results revealed an interplay of viral and cellular miRNAs to sequester each other from their respective targets. This is a novel mechanism for viruses to manipulate the expression of viral and cellular proteins, contributing to not only viral lytic and latent replication but also cell transformation observed in viral infectious diseases including oncogenesis

Dipalladium Complexes with Bridging Monoalkyl or Monophenyl Silyl Ligands in the Solid State and in Solution

HexSiH₃, PhSiH₃, and PhSiClH₂ reacted with [Pd­(PCy₃)₂] to yield dipalladium complexes with bridging silyl ligands: [{Pd­(PCy₃)}₂(μ-HSiXR)₂] (<b>1</b>, R = Hex, X = H; <b>2</b>, R = Ph, X = H; <b>3</b>, R = Ph, X = Cl). The X-ray crystallographic results displayed a typical bis­(silyl)-bridged dinuclear structure with an anti conformation of the substituents on the Si atom in the solid state. Temperature-dependent NMR spectroscopic analyses of <b>1</b> and <b>2</b> revealed a dynamic <i>syn</i>–<i>anti</i> isomerization of the complex via exchange of the bridging and nonbridging Si–H hydrogens in solution. Complex <b>3</b> with bridging chloro­(phenyl)­silyl ligands did not show such a dynamic behavior

Dipalladium Complexes with Bridging Monoalkyl or Monophenyl Silyl Ligands in the Solid State and in Solution

HexSiH₃, PhSiH₃, and PhSiClH₂ reacted with [Pd­(PCy₃)₂] to yield dipalladium complexes with bridging silyl ligands: [{Pd­(PCy₃)}₂(μ-HSiXR)₂] (<b>1</b>, R = Hex, X = H; <b>2</b>, R = Ph, X = H; <b>3</b>, R = Ph, X = Cl). The X-ray crystallographic results displayed a typical bis­(silyl)-bridged dinuclear structure with an anti conformation of the substituents on the Si atom in the solid state. Temperature-dependent NMR spectroscopic analyses of <b>1</b> and <b>2</b> revealed a dynamic <i>syn</i>–<i>anti</i> isomerization of the complex via exchange of the bridging and nonbridging Si–H hydrogens in solution. Complex <b>3</b> with bridging chloro­(phenyl)­silyl ligands did not show such a dynamic behavior