dolichols and Neoplasms

Glycoproteins are proteins that carry N- and O-glycosidically-linked carbohydrate chains of complex structures and functions. N-glycan chains are assembled in the endoplasmic reticulum and the Golgi by a controlled sequence of glycosyltransferase and glycosidase processing reactions involving dolichol intermediates. The assembly of O-glycans occurs in the Golgi and does not involve dolichol. For most reactions, families of glycosyltransferases exist; the expression of the individual enzymes within a family is often subject to complex regulation. The biosynthesis of N- and O-glycan is controlled at the level of gene expression, mRNA, enzyme protein activity and localization, and through substrate and cofactor concentrations at the site of synthesis. This complex regulation results in many hundreds of structures, the range of which varies in different species, cell types, tissue types, states of development and differentiation. In diseased cells, the relative proportions of these structures are often characteristically different from normal, and may be useful for the assessment of the stage of the disease and for diagnosis. Knowledge of disease-specific glycoprotein structures and their functions may be used therapeutically, in immunotherapy, in blocking cell adhesion or interfering with other binding or biological processes. Recently, some of the mechanisms underlying glycoprotein alterations in disease have been elucidated. This opens the possibility of an active interference in the disease process. The functions of glycans in diseased cells will become more clear with the tools of molecular biology and transgenic animal models.

Topics: Animals; Communicable Diseases; Congenital Disorders of Glycosylation; Dolichols; Endoplasmic Reticulum; Female; Glycoproteins; Glycosyltransferases; Golgi Apparatus; Humans; Inflammatory Bowel Diseases; Leukocyte-Adhesion Deficiency Syndrome; Male; Mice; Neoplasms; Phenotype; Polysaccharides; Transplantation, Heterologous; Vascular Diseases

Extrusion of chemotherapeutics by ATP-binding cassette (ABC) transporters like ABCB1 (P-glycoprotein) represents a crucial mechanism of multidrug resistance in cancer therapy. We have previously shown that the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor simvastatin directly inhibits ABCB1, alters the glycosylation of the transporter, and enhances the intracellular accumulation of doxorubicin with subsequent anti-cancer action. Here, we show that simvastatin reduces endogenous dolichol levels and ABCB1 in human neuroblastoma SH-SY5Y cells. Coapplication with dolichol prevents the downregulation of the ABCB1 transporter. Importantly, dolichol also attenuated simvastatin-induced apoptosis, unmasking involvement of unfolded protein response. Direct monitoring of the fluorescent fusion protein YFP-ABCB1 further confirms concentration-dependent reduction of ABCB1 in HEK293 cells by simvastatin. In simvastatin-treated murine xenografts, ABCB1 was also reduced in the liver and rhabdomyosarcoma but did not reach significance in neuroblastoma. Nevertheless, the in vivo anti-cancer effects of simvastatin are corroborated by increased apoptosis in tumor tissues. These findings provide experimental evidence for usage of simvastatin in novel chemotherapeutic regimens and link dolichol depletion to simvastatin-induced anti-cancer activity.

Topics: Animals; Antineoplastic Agents; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; Caspase 3; Cell Line, Tumor; Dolichols; Down-Regulation; Female; HEK293 Cells; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Liver; Mice; Neoplasms; Simvastatin; Tumor Burden

Agents that inhibit the synthesis of mevalonate or of downstream isoprenoids block the G1-S transition and induce apoptosis in many cell lines; these agents include statins, phenylacetate, and a range of cyclic and acyclic isoprenoids. This cytostatic effect is mediated primarily by decreased availability of dolichol; this deficit impedes the glycosylation of nascent IGF-I receptors, preventing their transfer to the cell surface. In most tissues as well as transformed cell lines, IGF-I activity is crucial for transition to S phase, and also prevents apoptosis. Thus, down-regulation of serum levels of free IGF-I - as may be achieved by caloric restriction, low-fat vegan diets, and various estrogen agonists/antagonists - may represent a useful strategy for preventing and controlling cancer; however, a compensatory up-regulation of tissue expression of IGF-I receptors limits the efficacy of such an approach. Concurrent use of agents that inhibit dolichol synthesis can be expected to prevent an increase in plasma membrane IGF-I receptors, thus potentiating the cancer-retardant efficacy of IGF-I down-regulation. Since dolichol and IGF-I appear to be essential for angiogenesis, these measures may also prove useful for control of pathogenic neovascularization.

Topics: Anticholesteremic Agents; Dolichols; Down-Regulation; Humans; Insulin-Like Growth Factor I; Mevalonic Acid; Neoplasms; Neovascularization, Pathologic; Sugar Phosphates

We studied the effect of seven different clinical diseases (viral infections, bacterial infections, malignant diseases, cardiovascular diseases, gastroenterological diseases, endocrinological diseases, and rheumatic diseases) as well as normal pregnancy on serum dolichol concentrations in 76 hospitalized patients and in 10 pregnant women. In contrast to urinary dolichols, serum dolichols were not significantly increased in any of these conditions, suggesting that dolichol levels in serum and urine are independently regulated. Furthermore, we found that serum dolichol concentration does not undergo diurnal variation, as in healthy volunteers time of blood sampling did not affect serum dolichols. Our results suggest that serum dolichol concentration, which has earlier been found to be exceptionally high in aspartylglucosaminuria and mannosidosis, might serve as a laboratory marker for these recessively inherited lysosomal storage diseases.

Topics: Adult; Bacterial Infections; Cardiovascular Diseases; Dolichols; Endocrine System Diseases; Female; Gastrointestinal Diseases; Humans; Male; Neoplasms; Pregnancy; Reference Values; Rheumatic Diseases; Virus Diseases

The effect of different clinical conditions on urinary dolichols was studied in 219 hospital patients and in 24 pregnant women. Significantly increased urinary dolichol levels were found in patients with severe bacterial infections (mean +/- SEM, 37.5 +/- 8.0 micrograms/mmol creatinine, P less than 0.001), in patients with haematological or metastatic (23.3. +/- 5.1, P less than 0.05) as well as localised (15.4 +/- 1.8, P less than 0.01) malignancies and in pregnant women (22.2 +/- 1.8, P less than 0.001) as compared to healthy controls (6.6 +/- 0.4). These results show that urinary excretion of dolichols may be increased, not only in alcoholics and patients with some rare neurodegenerative storage diseases, but also in patients suffering from various other diseases.

Topics: Adult; Aged; Bacterial Infections; Dolichols; Female; Humans; Leukemia; Lymphoma; Male; Middle Aged; Neoplasms; Pregnancy