Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In view of the increasing evidence that glucosphingolipids (GSLs) on tumor cell surfaces play an important role in tumor metastasis, an inhibitor of glucosylceramide synthase, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) was used to evaluate the role of GSLs in this respect. Treatment of Lewis lung carcinoma cells with 5 microM D-PDMP resulted in a time-dependent marked decrease in levels of all cellular GSLs (glucosylceramide, lactosylceramide, ceramide trihexoside, globoside, and ganglioside GM3). By 6 days, the total GSL content was reduced to approximately 20% of the level in the untreated control cells and at the same time the lung-colonizing capacity of the PDMP-treated cells in inoculated mice was greatly reduced. Closely associated with the degree of GSL depletion, the ability of the cells to invade reconstituted basement membranes in vitro was also reduced, suggesting that GSLs in tumor cell membranes modulate the cell surface interaction with basement membrane components. In order to assess a possible contribution of the defective capacities to drug-induced suppression of experimental metastasis and invasion, we tested the effect of D-PDMP on attachment and migration to laminin and fibronectin and found that the inhibitor specifically reduced the laminin-mediated attachment and migration, whereas it had no effect on fibronectin-mediated attachment and migration. These effects of the inhibitor on lung colonizing capacity in vivo and the invasion, adhesion, and migration properties of the cells in vitro were reversible within 24 h after removal of the drug. By contrast, L-PDMP (the enantiomeric form of D-PDMP), which has no inhibitory activity on glucosylceramide synthesis, did not cause any of the changes produced by D-PDMP. Together, these results suggest that GSLs in tumor cell membranes are essential for the metastatic spread of tumor cells through basement membranes, modulating the interaction of laminin and its receptors.
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PMID:Inhibition of experimental metastasis of murine Lewis lung carcinoma by an inhibitor of glucosylceramide synthase and its possible mechanism of action. 214 65

In view of the evidence that cell expression of gangliosides in several tumors is positively involved in the metastatic phenotype, Lewis lung carcinoma (3LL) cell line, expressing GM3 as the major ganglioside, was analysed for the cell surface expression of GM3. An indirect immunofluorescence assay, using a M2590 monoclonal antibody recognizing GM3, was used for this purpose. Since the parental 3LL cells consist of heterogenous subpopulations differing in the degrees of GM3 expression, we have developed clones of this cell line with different degrees of metastatic potentials by using an in vitro non-selective procedure in order to investigate whether the expression of GM3 is associated with metastatic potential. The degree of cell surface expression of GM3 among the clones correlated well with their total cellular content of this ganglioside. However, we were unable to confirm the report of increased level of GM3 in high metastatic 3LL clones, nor did a decreased level correlate with weak metastatic ability. In our recent work, an inhibitor of glucosylceramide synthase, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), was found to decrease the levels of all cellular glucosphingolipids and cause the accumulation of the precursors of glucosylceramide. The present study does not, however, rule out the possible involvement of this lipid family in metastatic dissemination, since treatment of 3LL cells with D-PDMP resulted in significant inhibition of their experimental metastatic potential. Clones expressing very low GM3 grew slowly in culture dishes, suggesting that GM3 may have a regulatory role in cell proliferation. The low metastatic clones expressed high levels of H-2Kb antigen, while the expression of the same antigen on the high metastatic clones was relatively low, confirming the previous observation of this tumor system. Moreover, a clone showing the lowest tumorigenic potency revealed both a high cell surface expression of H-2Kb and a high H-2Kb/H-2Db ratio.
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PMID:Expression of ganglioside GM3 and H-2 antigens in clones with different metastatic and growth potentials isolated from Lewis lung carcinoma (3LL) cell line. 842 3

In view of the increasing evidence that gangliosides in membrane microdomains or rafts are closely associated with various signal transducing molecules including Src family kinases, we compared rafts in two subclones of 3LL mouse lung carcinoma cell line, J18 and J5, characterized by high and very low GM3 ganglioside contents, respectively. Rafts were isolated from cell lysates as low density detergent-insoluble microdomains (DIM) by sucrose density gradient centrifugation. J5 and J18 cells expressed comparable amounts of Src family kinases and the majority of Src kinases in both clones were concentrated in their DIMs, suggesting that GM3 is not necessary for DIM localization of Src kinases and there is no direct interaction between Src and GM3. However, the Src kinases were eliminated from DIMs after depletion of the major neutral GSLs of J5 cells, glucosylceramide and lactosylceramide, by an inhibitor of glucosylceramide synthase (D-PDMP), indicating that GSLs in general are required for Src kinase association to DIM. J5 and the D-PDMP-treated J5 cells had very similar DIM protein profiles and moreover cholesterol and sphingomyelin in the GSL-depleted cells were enriched in DIM similar to the untreated control cells. Interestingly, the levels of tyrosine-phosphorylated DIM proteins and cell proliferation of J5 cells were much lower than those of J18 cells, suggesting that GM3 might be involved in tyrosine phosphorylation of DIM proteins required for cell growth. Thus, our data suggest that GSLs are essential for functional raft formation.
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PMID:Glycosphingolipid deficiency affects functional microdomain formation in Lewis lung carcinoma cells. 1120 96

Although the molecular function of sigma receptors has not been fully defined and the natural ligand(s) is still not known, there is increasing evidence that these receptors and their ligands might play a significant role in cancer biology. 4-(N-benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP), a selective sigma1 agonist, has been used to investigate whether this compound is able to modify: 1) in vitro the migration and proliferation of human cancer cells; 2) in vitro the sensitivity of human glioblastoma cells to cytotoxic drugs; and 3) in vivo in orthotopic glioblastoma and non-small cell lung carcinoma (NSCLC) models the survival of mice co-administered cytotoxic agents. 4-IBP has revealed weak antiproliferative effects on human U373-MG glioblastoma and C32 melanoma cells but induced marked concentration-dependent decreases in the growth of human A549 NSCLC and PC3 prostate cancer cells. The compound was also significantly antimigratory in all four cancer cell lines. This may result, at least in U373-MG cells, from modifications to the actin cytoskeleton. 4-IBP modified the sensitivity of U373-MG cells in vitro to proapoptotic lomustin and proautophagic temozolomide, and markedly decreased the expression of two proteins involved in drug resistance: glucosylceramide synthase and Rho guanine nucleotide dissociation inhibitor. In vivo, 4-IBP increased the antitumor effects of temozolomide and irinotecan in immunodeficient mice that were orthotopically grafted with invasive cancer cells.
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PMID:4-IBP, a sigma1 receptor agonist, decreases the migration of human cancer cells, including glioblastoma cells, in vitro and sensitizes them in vitro and in vivo to cytotoxic insults of proapoptotic and proautophagic drugs. 1778 88