title: Iodide excess induces apoptosis in thyroid cells through a p53-independent mechanism involving oxidative stress.
abstract: Thyroid toxicity of iodide excess has been demonstrated in animals fed with an iodide-rich diet; in vitro iodide is cytotoxic, inhibits cell growth, and induces morphological changes in thyroid cells of some species. In this study, we investigated the effect of iodide excess in an immortalized thyroid cell line (TAD-2) in primary cultures of human thyroid cells and in cells of nonthyroid origin. Iodide displayed a dose-dependent cytotoxicity in both TAD-2 and primary thyroid cells, although at different concentrations, whereas it had no effect on cells of nonthyroid origin. Thyroid cells treated with iodide excess underwent apoptosis, as evidenced by morphological changes, plasma membrane phosphatidylserine exposure, and DNA fragmentation. Apoptosis was unaffected by protein synthesis inhibition, whereas inhibition of peroxidase enzymatic activity by propylthiouracil completely blocked iodide cytotoxicity. During KI treatment, reactive oxygen species were produced, and lipid peroxide levels increased markedly. Inhibition of endogenous p53 activity did not affect the sensitivity of TAD-2 cells to iodide, and Western blot analysis demonstrated that p53, Bcl-2, Bcl-XL, and Bax protein expression did not change when cells were treated with iodide. These data indicate that excess molecular iodide, generated by oxidation of ionic iodine by endogenous peroxidases, induces apoptosis in thyroid cells through a mechanism involving generation of free radicals. This type of apoptosis is p53 independent, does not require protein synthesis, and is not induced by modulation of Bcl-2, Bcl-XL, or Bax protein expression.
authors.affiliation: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università Federico II, Naples, Italy. mavitale@unina.it
authors.forename: M
authors.initials: M
authors.lastname: Vitale
authors.forename: T
authors.initials: T
authors.lastname: Di Matola
authors.forename: F
authors.initials: F
authors.lastname: D'Ascoli
authors.forename: S
authors.initials: S
authors.lastname: Salzano
authors.forename: F
authors.initials: F
authors.lastname: Bogazzi
authors.forename: G
authors.initials: G
authors.lastname: Fenzi
authors.forename: E
authors.initials: E
authors.lastname: Martino
authors.forename: G
authors.initials: G
authors.lastname: Rossi
mesh_terms: D017304:Annexin A5 / Q000032:analysis; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007453:Iodide Peroxidase / Q000378:metabolism; D007700:Kinetics; D009336:Necrosis; D018384:Oxidative Stress / Q000502:physiology*; D010718:Phosphatidylserines / Q000378:metabolism; D011193:Potassium Iodide / Q000633:toxicity*; D011441:Propylthiouracil / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013961:Thyroid Gland / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
chemical_list: D017304:Annexin A5; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D010718:Phosphatidylserines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D011193:Potassium Iodide; D011441:Propylthiouracil; D003513:Cycloheximide; D007453:Iodide Peroxidase