Use of a glycolipid inhibitor to ameliorate renal cancer in a mouse model

• Published in: PloS one 2013-05, Vol.8 (5), p.e63726-e63726
• Main Authors: Chatterjee, Subroto, Alsaeedi, Nezar, Hou, Jennifer, Bandaru, Veera Venkata Ratnam, Wu, Lan, Halushka, Marc K, Pili, Roberto, Ndikuyeze, Georges, Haughey, Norman J
• Format: Article
• Language: English
• Subjects: Administration, Oral; AKT protein; AKT1 protein; Angiogenesis; Animals; Antigens, CD - metabolism; Apoptosis; Biology; Biosynthesis; Blotting, Western; Cancer; Cardiology; Cell growth; Cell proliferation; Ceramide glucosyltransferase; Disease Models, Animal; Disease Progression; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - pharmacology; Galactosyltransferases - antagonists & inhibitors; Galactosyltransferases - metabolism; Gangliosides; Gene expression; Glucosylceramides - metabolism; Glucosyltransferases - antagonists & inhibitors; Glucosyltransferases - metabolism; Inhibitors; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Kidney cancer; Kidney diseases; Kidney Neoplasms - drug therapy; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Kidneys; Kinases; Lactosylceramides - metabolism; Medical research; Medicine; Mice; Mice, Inbred BALB C; Morpholines - administration & dosage; Morpholines - pharmacology; Pediatrics; Peptide Fragments - metabolism; Propanol; Proto-Oncogene Proteins c-akt - metabolism; Rapamycin; Rodents; Signal Transduction - drug effects; Surgery; Synthesis; Time Factors; TOR protein; Transcription Factors; Treatment Outcome; Tumor Burden - drug effects; Tumor Suppressor Protein p53 - metabolism; Tumors; Vascular endothelial growth factor; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0063726

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.