title: Aberrant apoptosis in thyroid epithelial cells from goiter nodules.
abstract: The specific pathogenesis of nodular goiter and the role of apoptosis in goitrogenesis are not known. We sought to examine the regulation of the TNF-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL)-induced apoptosis pathways in primary thyroid cells from 17 patients with nodular goiter, using 10 normal thyroids as controls. Both goitrous and normal thyroid cells were resistant to recombinant human TRAIL and an agonist anti-Fas antibody under basal conditions. However, all normal thyrocytes could be sensitized by TNFalpha/IL-1beta or interferon gamma/IL-1beta to undergo apoptosis in response to TRAIL or FasL, respectively. In contrast, the majority of goiter-derived cells remained resistant to TRAIL (12 of 17 samples) or FasL (9 of 17 samples) after cytokine pretreatment; 14 of 17 goiter nodules were resistant to at least one death ligand. Goiter size was inversely correlated with the sensitivity to TRAIL-mediated apoptosis. The resistance of goiter cells to TRAIL did not appear to be due to transcriptional regulation or cell surface expression of death and decoy receptors. However, increased proteasome activity was found in a subset of goiter cells resistant to both death ligands, and proteasome inhibitors could sensitize these goiter cells to TRAIL-mediated apoptosis. In conclusion, goiter-derived thyroid cells are resistant to TRAIL and/or Fas-induced apoptosis in vitro, and this may represent a new aspect of aberrant growth regulation in goiter nodules. The increased proteasome activity associated with this resistance suggests that the proteasome may be an important regulator of apoptosis in nodular goiter.
authors.affiliation: Department of Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0648, USA.
authors.forename: Emese
authors.initials: E
authors.lastname: Mezosi
authors.forename: Hiroko
authors.initials: H
authors.lastname: Yamazaki
authors.forename: James D
authors.initials: JD
authors.lastname: Bretz
authors.forename: Su He
authors.initials: SH
authors.lastname: Wang
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Arscott
authors.forename: Saho
authors.initials: S
authors.lastname: Utsugi
authors.forename: Paul G
authors.initials: PG
authors.lastname: Gauger
authors.forename: Norman W
authors.initials: NW
authors.lastname: Thompson
authors.forename: James R
authors.initials: JR
authors.lastname: Baker
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D006044:Goiter, Nodular / Q000276:immunology / Q000473:pathology* / Q000601:surgery; D006801:Humans; D015151:Immunoblotting; D007371:Interferon-gamma / Q000494:pharmacology; D007633:Keratins / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D011994:Recombinant Proteins; D012016:Reference Values; D053221:TNF-Related Apoptosis-Inducing Ligand; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D013965:Thyroidectomy; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D019014:fas Receptor / Q000032:analysis
chemical_list: D051017:Apoptosis Regulatory Proteins; D015853:Cysteine Proteinase Inhibitors; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C067713:lactacystin; D007633:Keratins; D007371:Interferon-gamma; D000111:Acetylcysteine