title: Biotin deficiency stimulates survival pathways in human lymphoma cells exposed to antineoplastic drugs.
abstract: Cells may respond to nutrient deficiency or death signals with nuclear translocation of the transcription factor nuclear factor kappaB (NF-kappaB), which activates transcription of anti-apoptotic genes. Here we tested the hypothesis that biotin deficiency stimulates NF-kappaB-dependent survival pathways in human lymphoma cells, enhancing resistance to antineoplastic agents. Lymphoma (Jurkat) cells were cultured in biotin-deficient (0.025 nmol/L) and biotin-supplemented (10 nmol/L) media. If cells were treated with antineoplastic agents (taxol, doxorubicin or vinblastine), nuclear translocation of two NF-kappaB proteins (p50 and p65) was >25% greater in biotin-deficient compared with biotin-supplemented cells. The transcriptional activities of the following NF-kappaB-dependent reporter genes were 16-59% greater in biotin-deficient compared with biotin-supplemented cells treated with various antineoplastic agents: (1) reporter expression driven by a TATA box and five NF-kappaB repeats and (2) reporter expression driven by the regulatory region of the anti-apoptotic Bfl-1 gene. Collectively, these findings are consistent with activation of survival pathways in biotin-deficient lymphoma cells. Finally, cells were treated with antineoplastic agents for 48 h and cell survival was monitored at timed intervals. Biotin deficiency was associated with enhanced survival of cells treated with doxorubicin and vinblastine, but did not affect survival of cells treated with taxol. Collectively, these observations suggest that biotin deficiency may enhance resistance of cancer cells to antineoplastic agents.
authors.affiliation: Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583-0806, USA.
authors.forename: Jacob B
authors.initials: JB
authors.lastname: Griffin
authors.forename: Janos
authors.initials: J
authors.lastname: Zempleni
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D001692:Biological Transport / Q000187:drug effects; D001710:Biotin / Q000008:administration & dosage / Q000172:deficiency* / Q000502:physiology; D019921:Biotinylation; D002262:Carboxy-Lyases / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects*; D003470:Culture Media; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D019169:Jurkat Cells; D008156:Luciferases / Q000235:genetics; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C096816:BCL2-related protein A1; D003470:Culture Media; D015778:Minor Histocompatibility Antigens; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D014747:Vinblastine; D001710:Biotin; D004317:Doxorubicin; D008156:Luciferases; D002262:Carboxy-Lyases