12 patients who had histological proven ganglioneuromas were investigated by computed tomography (CT) and magnetic resonance (MR) imaging. CT scans (n = 11), conventional spin-echo MR images (n = 10) and dynamic MR images (n = 5) were acquired. All lesions showed a well defined, oval shape. Five lesions (42%) showed calcification which was punctate in four and coarse in one on CT. CT attenuation was predominantly low in three of 10 (30%) and intermediate in the remaining seven (70%). In all lesions MR signals were mainly of low intensity on T1 weighted images (T1WI) and of high intensity on T2 weighted images (T2WI). Dynamic MR studies in five cases showed a lack of early enhancement but gradual increasing enhancement. One case had a ganglioneuroblastoma component which showed soft-tissue density and coarse calcifications on CT scans, MR images with intermediate intensity on T1WI and T2WI and early enhancement and little washout on dynamic MR images. In conclusion, ganglioneuroma typically shows punctate calcification and low attenuation on CT and marked hyperintensity on T2WI with gradual increasing enhancement on dynamic MR images. If a ganglioneuroma has atypical CT and MR features, coexistence of a malignant component should be considered.
Binding of Escherichia coli chaperonin, GroEL, to substrate proteins with non-native structure, reduced ␣-lactalbumin (rLA) and denatured pepsin, were analyzed by isothermal titration calorimetry at various temperatures in the presence of salt (0.2 M KCl). Both proteins bound to GroEL with 1:1 stoichiometry and micromolar affinity at all temperatures tested. However, thermodynamic properties of their binding to GroEL are remarkably different from each other. While heat capacity changes (⌬Cp) of rLA-GroEL binding showed large negative values, ؊4.19 kJ mol ؊1 K ؊1, that of denatured pepsin-GroEL binding was only ؊0.2 kJ mol ؊1 K ؊1 . These values strongly indicate that the hydrophobic interaction is a major force of rLA-GroEL binding but not so for denatured pepsin-GroEL binding. When salt was omitted from the solution, the affinity and ⌬Cp of the rLA-GroEL binding reaction were not significantly changed whereas denatured pepsin lost affinity to GroEL. Thus, in the non-native protein-GroEL binding reaction, thermodynamic properties, as well as the effect of salt, differ from protein to protein and hydrophobic interaction may not always be a major driving force.
Expression of human protein kinase C delta (PKCδ) protein has been linked to many types of cancers. PKCδ is known to be a multifunctional PKC family member and has been rigorously studied as an intracellular signaling molecule. Here we show that PKCδ is a secretory protein that regulates cell growth of liver cancer. Full-length PKCδ was secreted to the extracellular space in living liver cancer cells under normal cell culture conditions and in xenograft mouse models. Patients with liver cancer showed higher levels of serum PKCδ than patients with chronic hepatitis or liver cirrhosis or healthy individuals. In liver cancer cells, PKCδ secretion was executed in an endoplasmic reticulum (ER)-Golgi–independent manner, and the inactivation status of cytosolic PKCδ was required for its secretion. Furthermore, colocalization studies showed that extracellular PKCδ was anchored on the cell surface of liver cancer cells via association with glypican 3, a liver cancer–related heparan sulfate proteoglycan. Addition of exogenous PKCδ activated IGF-1 receptor (IGF1R) activation and subsequently enhanced activation of ERK1/2, which led to accelerated cell growth in liver cancer cells. Conversely, treatment with anti-PKCδ antibody attenuated activation of both IGF1R and ERK1/2 and reduced cell proliferation and spheroid formation of liver cancer cells and tumor growth in xenograft mouse models. This study demonstrates the presence of PKCδ at the extracellular space and the function of PKCδ as a growth factor and provides a rationale for the extracellular PKCδ-targeting therapy of liver cancer. Significance: PKCδ secretion from liver cancer cells behaves as a humoral growth factor that contributes to cell growth via activation of proliferative signaling molecules, which may be potential diagnostic or therapeutic targets.
Abstract. Ovarian clear cell carcinoma (OCCC) has several significant characteristics based on molecular features that are distinct from those of ovarian high-grade serous carcinoma. Cellular glycogen accumulation is the most conspicuous feature of OCCC and in the present study its metabolic mechanism was investigated. The amount of glycogen in cells cultured under hypoxia increased significantly and approximately doubled after 48 h (P<0.01) compared to that under normoxic conditions. Periodic acid-Schiff positive staining also demonstrated intracellular glycogen storage. Western blot analysis revealed that HIF1α, which was overexpressed and stabilized under hypoxic conditions, led to an increase in the levels of cellular glycogen synthase 1, muscle type (GYS1), and conversely to a decrease in inactive phosphorylated GYS1 at serine (Ser) 641. Additional increases were observed in both protein phosphatase 1, which dephosphorylates and thereby induces GYS1 enzyme activity, and glycogen synthase kinase 3 beta (GSK3β) phosphorylated at Ser9, which is inactive on phosphorylation of GYS1 and subsequently induces its enzyme activity. By contrast, the level of PYGM-b decreased. These results indicated that the glycogen accumulation under a hypoxic environment resulted in the promotion of glycogen synthesis, but did not lead to inhibition of glycogen degradation and/or consumption. Under hypoxic conditions, HAC2 cells showed activation of the PI3K/AKT pathway caused by a mutation in exon 20 of PIK3CA, encoding the catalytic subunit p110α of PI3K. The resulting activation of AKT (phosphoSer473) also plays a role as a central enhancer in glycogen synthesis through suppression of GSK3β via phosphorylation at Ser9. Hypoxia decreased the cytocidal activity of cisplatin and doxorubicin to various degrees. In conclusion, the hypoxic conditions together with HIF1 expression and stabilization increased the intracellular glycogen contents and resistance to the anticancer drugs.
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