Abstract
In a xenograft model wherein, live renal cancer cells were implanted under the kidney capsule in mice, revealed a 30-fold increase in tumor volume over a period of 26 days and this was accompanied with a 32-fold increase in the level of lactosylceramide (LacCer). Mice fed D- threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP), an inhibitor of glucosylceramide synthase and lactosylceramide synthase (LCS: β-1,4-GalT-V), showed marked reduction in tumor volume. This was accompanied by a decrease in the mass of lactosylceramide and an increase in glucosylceramide (GlcCer) level. Mechanistic studies revealed that D-PDMP inhibited cell proliferation and angiogenesis by inhibiting p44MAPK, p-AKT-1 pathway and mammalian target for rapamycin (mTOR). By linking glycosphingolipid synthesis with tumor growth, renal cancer progression and regression can be evaluated. Thus inhibiting glycosphingolipid synthesis can be a bonafide target to prevent the progression of other types of cancer.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Antigens, CD / metabolism
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Blotting, Western
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Disease Models, Animal*
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Disease Progression
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Enzyme Inhibitors / administration & dosage
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Enzyme Inhibitors / pharmacology*
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Galactosyltransferases / antagonists & inhibitors
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Galactosyltransferases / metabolism
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Glucosylceramides / metabolism
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Glucosyltransferases / antagonists & inhibitors
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Glucosyltransferases / metabolism
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Kidney / drug effects*
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Kidney / metabolism
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Kidney / pathology
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Kidney Neoplasms / drug therapy*
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Kidney Neoplasms / metabolism
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Kidney Neoplasms / pathology
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Lactosylceramides / metabolism
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Mice
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Mice, Inbred BALB C
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Morpholines / administration & dosage
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Morpholines / pharmacology*
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Peptide Fragments / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Signal Transduction / drug effects
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Time Factors
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Transcription Factors
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Treatment Outcome
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Tumor Burden / drug effects
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Tumor Suppressor Protein p53 / metabolism
Substances
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Antigens, CD
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Enzyme Inhibitors
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Glucosylceramides
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Lactosylceramides
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Morpholines
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Peptide Fragments
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Transcription Factors
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Tumor Suppressor Protein p53
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WDR77 protein, mouse
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CDw17 antigen
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RV 538
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Galactosyltransferases
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Glucosyltransferases
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UDPgalactose-glucosylceramide galactosyltransferase
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ceramide glucosyltransferase
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Proto-Oncogene Proteins c-akt