title: C282Y-HFE gene variant affects cholesterol metabolism in human neuroblastoma cells.
abstract: Although disruptions in the maintenance of iron and cholesterol metabolism have been implicated in several cancers, the association between variants in the HFE gene that is associated with cellular iron uptake and cholesterol metabolism has not been studied. The C282Y-HFE variant is a risk factor for different cancers, is known to affect sphingolipid metabolism, and to result in increased cellular iron uptake. The effect of this variant on cholesterol metabolism and its possible relevance to cancer phenotype was investigated using wild type (WT) and C282Y-HFE transfected human neuroblastoma SH-SY5Y cells. Expression of C282Y-HFE in SH-SY5Y cells resulted in a significant increase in total cholesterol as well as increased transcription of a number of genes involved in its metabolism compared to cells expressing WT-HFE. The marked increase in expression of NPC1L1 relative to that of most other genes, was accompanied by a significant increase in expression of NPC1, a protein that functions in cholesterol uptake by cells. Because inhibitors of cholesterol metabolism have been proposed to be beneficial for treating certain cancers, their effect on the viability of C282Y-HFE neuroblastoma cells was ascertained. C282Y-HFE cells were significantly more sensitive than WT-HFE cells to U18666A, an inhibitor of desmosterol Δ24-reductase the enzyme catalyzing the last step in cholesterol biosynthesis. This was not seen for simvastatin, ezetimibe, or a sphingosine kinase inhibitor. These studies indicate that cancers presenting in carriers of the C282Y-HFE allele might be responsive to treatment designed to selectively reduce cholesterol content in their tumor cells.
authors.affiliation: Department of Neurosurgery, The Pennsylvania State University College of Medicine, Penn State Hershey Cancer Institute, Penn State M.S. Hershey Medical Center, Hershey, Pennsylvania, United States of America.
authors.forename: Fatima
authors.initials: F
authors.lastname: Ali-Rahmani
authors.affiliation: Division of Pediatric Hematology/Oncology, The Pennsylvania State University College of Medicine, Penn State Hershey Cancer Institute, Penn State M.S. Hershey Medical Center, Hershey, Pennsylvania, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Penn State Hershey Cancer Institute, Penn State M.S. Hershey Medical Center, Hershey, Pennsylvania, United States of America.
authors.forename: C-L
authors.initials: CL
authors.lastname: Schengrund
authors.affiliation: Department of Neurosurgery, The Pennsylvania State University College of Medicine, Penn State Hershey Cancer Institute, Penn State M.S. Hershey Medical Center, Hershey, Pennsylvania, United States of America.
authors.forename: James R
authors.initials: JR
authors.lastname: Connor
authors.affiliation: Department of Neurosurgery, The Pennsylvania State University College of Medicine, Penn State Hershey Cancer Institute, Penn State M.S. Hershey Medical Center, Hershey, Pennsylvania, United States of America.
authors.forename: Sang Y
authors.initials: SY
authors.lastname: Lee
mesh_terms: D000483:Alleles; D000736:Androstenes / Q000737:chemistry; D001384:Azetidines / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival; D002784:Cholesterol / Q000378:metabolism*; D000069438:Ezetimibe; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007501:Iron / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D009447:Neuroblastoma / Q000235:genetics*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010641:Phenotype; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors; D012307:Risk Factors; D019821:Simvastatin / Q000737:chemistry; D013107:Sphingolipids / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D000736:Androstenes; D001384:Azetidines; D002784:Cholesterol; D000069438:Ezetimibe; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D007501:Iron; D008565:Membrane Proteins; D010088:Oxidoreductases; D017853:Phosphotransferases (Alcohol Group Acceptor); D019821:Simvastatin; D013107:Sphingolipids; D000099157:Sphingosine Kinase; C103673:HFE protein, human; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; C022673:delta 24-sterol reductase