dolichols and Cell-Transformation--Neoplastic

Neurite outgrowth inhibitor-B (Nogo-B) is a membrane protein which is extensively expressed in multiple organs, especially in endothelial cells and vascular smooth muscle cells of blood vessels and belongs to the reticulon protein family. Notably, its specific receptor, Nogo-B receptor (NgBR), encoded by NUS1, has been implicated in many crucial cellular processes, such as cholesterol trafficking, lipid metabolism, dolichol synthesis, protein N-glycosylation, vascular remodelling, angiogenesis, tumorigenesis and neurodevelopment. In recent years, accumulating studies have demonstrated the statistically significant changes of NgBR expression levels in human diseases, including Niemann-Pick type C disease, fatty liver, congenital disorders of glycosylation, persistent pulmonary hypertension of the newborn, invasive ductal breast carcinoma, malignant melanoma, non-small cell lung carcinoma, paediatric epilepsy and Parkinson's disease. Besides, both the in vitro and in vivo studies have shown that NgBR overexpression or knockdown contribute to the alteration of various pathophysiological processes. Thus, there is a broad development potential in therapeutic strategies by modifying the expression levels of NgBR.

Topics: Animals; Biological Transport; Cell Transformation, Neoplastic; Cholesterol; Disease Susceptibility; Dolichols; Gene Expression Regulation; Glycosylation; Humans; Lipid Metabolism; Nervous System; Nogo Proteins; Protein Binding; Receptors, Cell Surface; Research; Signal Transduction

Serum depletion of exponentially growing normal human fibroblasts resulted in a moderate depression of the activity of HMG-CoA reductase which occurred simultaneously to the onset of growth arrest of the cells. Specific inhibition of HMG-CoA reductase using mevinolin also resulted in growth arrest. PDGF counteracted the suppressive effect of serum depletion on HMG-CoA reductase activity and cell growth. The growth inhibitory effect of serum depletion and mevinolin was correlated to a decreased biosynthesis of dolichols, in particular of dolichol-20. If PDGF was present in the serum-free medium a high rate of dolichol synthesis was maintained. This effect was mediated not only through an increased HMG-CoA reductase activity. PDGF also increased the incorporation of mevalonate into dolichols, once again into dolichol-20 in particular. In contrast to HDF, the growth of virus-transformed human fibroblasts was not decreased following serum depletion. This was correlated to a sustained activity of HMG-CoA reductase and a sustained dolichol-20 synthesis. In order to block growth and dolichol synthesis of the transformed fibroblasts a stronger inhibition of HMG-CoA reductase activity was required than in the normal cells. Conditioned medium isolated from the transformed cells was found to maintain a high growth rate and a high HMG-CoA reductase activity in serum-depleted HDF. In addition, the incorporation of mevalonate into dolichols was increased. The present data raise the possibility that PDGF or related factors, through autocrine loops, may contribute to the maintenance of a high dolichol synthesis in tumor cells.

Topics: Butadienes; Cell Division; Cell Line; Cell Transformation, Neoplastic; Cell Transformation, Viral; Culture Media; Dolichols; Fibroblasts; Hemiterpenes; Humans; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin; Mevalonic Acid; Pentanes; Platelet-Derived Growth Factor; Simian virus 40

The content of dolichol in thymus gland of mice increased up to four times upon malignant transformation evoked by X-ray irradiation of animals or/and in the case of spontaneous tumours as compared with normal thymus. Dolichyl phosphate mannose and dolichyl pyrophosphate N-acetylglucosamine were formed in homogenates of transformed thymus at a higher rate than in normal gland.

Topics: Animals; Cell Transformation, Neoplastic; Diterpenes; Dolichol Monophosphate Mannose; Dolichol Phosphates; Dolichols; Mice; Mice, Inbred C57BL; Polyisoprenyl Phosphate Sugars; Polyisoprenyl Phosphates; Thymus Neoplasms; X-Rays

Topics: Animals; Cell Transformation, Neoplastic; Dolichols; Glucose; In Vitro Techniques; Lipid Metabolism; Liver Neoplasms; Microsomes, Liver; Proteins; Rats

Incubation of SV40-transformed human lung fibroblasts with [3H]glucosamine for 1 h. followed by chloroform:methanol extraction and thin layer chromatographic analysis, revealed the presence of a major radioactive lipid that was isolated and characterized as GIcUA-(1 leads to 4)-GlcNAc-P-P-dolichol. An identical lipid was formed in smaller quantities under similar incubation conditions in several fibroblastic lines, HeLa cells, and in mouse L cells. Rat lung microsomal preparations catalyze the synthesis of the disaccharide lipid in the following sequence of reactions: UDP-[3H]GlcNAc + dolichol-P leads to [3H]GlcNAc-P-P-dolichol (1) [3H]GlcNAc-P-P-dolichol + UDP-[14C]GlcUA leads to [14C]GlcUA-[3H]GlcNAc-P-P-dolichol (2) The double-labeled lipid was identical to the lipid isolated from SV40-transformed fibroblasts with regard to its behavior on thin layer and silicic acid chromatography. Further, the double-labeled disaccharide released from the lipid by mild acid hydrolysis was identical to GlcUA-(1 leads to 4)-GlcNAc in its chromatographic and electrophoretic behavior and in its composition. The occurrence of a polyprenol derivative of GlcUA-(1 leads to 4)-GlcNAc suggests a possible role for this lipid in the biosynthesis of the repeating disaccharide units of proteoglycans, such as heparin.

Topics: Animals; Cell Line; Cell Transformation, Neoplastic; Diterpenes; Dolichols; Fibroblasts; Glucosamine; Glucosephosphates; Humans; Lipids; Lung; Male; Microsomes; Polyisoprenyl Phosphate Oligosaccharides; Protein Biosynthesis; Rats; Simian virus 40