title: HFE polymorphisms influence the response to chemotherapeutic agents via induction of p16INK4A.
abstract: HFE is a protein that impacts cellular iron uptake. HFE gene variants are identified as risk factors or modifiers for multiple diseases. Using HFE stably transfected human neuroblastoma cells, we found that cells carrying the C282Y HFE variant do not differentiate when exposed to retinoic acid. Therefore, we hypothesized HFE variants would impact response to therapeutic agents. Both the human neuroblastoma and glioma cells that express the C282Y HFE variant are resistant to Temodar, geldanamycin and γ-radiation. A gene array analysis revealed that p16INK4A (p16) expression was increased in association with C282Y expression. Decreasing p16 protein by siRNA resulted in increased vulnerability to all of the therapeutic agents suggesting that p16 is responsible for the resistance. Decreasing HFE expression by siRNA resulted in a 85% decrease in p16 expression in the neuroblastoma cells but not the astrocytoma cells. These data suggest a potential direct relationship between HFE and p16 that may be cell specific or mediated by different pathways in the different cell types. In conclusion, the C282Y HFE variant impacts the vulnerability of cancer cells to current treatment strategies apparently by increasing expression of p16. Although best known as a tumor suppressor, there are multiple reports that p16 is elevated in some forms of cancer. Given the frequency of the HFE gene variants, as high as 10% of the Caucasian population, these data provide compelling evidence that the C282Y HFE variant should be part of a pharmacogenetic strategy for evaluating treatment efficacy in cancer cells.
authors.affiliation: Department of Neurosurgery, The Pennsylvania State University College of Medicine, MS Hershey Medical Center, Hershey, PA 17033-0850, USA. syl3@psu.edu
authors.forename: Sang Y
authors.initials: SY
authors.lastname: Lee
authors.forename: Siying
authors.initials: S
authors.lastname: Liu
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Mitchell
authors.forename: Becky
authors.initials: B
authors.lastname: Slagle-Webb
authors.forename: Young-Soo
authors.initials: YS
authors.lastname: Hong
authors.forename: Jonas M
authors.initials: JM
authors.lastname: Sheehan
authors.forename: James R
authors.initials: JR
authors.lastname: Connor
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D020869:Gene Expression Profiling; D005910:Glioma / Q000188:drug therapy / Q000235:genetics; D050884:HSP72 Heat-Shock Proteins / Q000235:genetics; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011836:Radiation Tolerance / Q000235:genetics; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; C103673:HFE protein, human; D050884:HSP72 Heat-Shock Proteins; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D004317:Doxorubicin; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide