title: Selenium decreases thyroid cancer cell growth by increasing expression of GADD153 and GADD34.
abstract: Selenium (Se) supplementation is reported to decrease the incidence and total mortality of cancer. Whereas in vitro and in vivo studies have shown a decrease in prostate, lung, and liver cancers, this has not been shown in thyroid cancer. ARO (anaplastic), NPA (BRAF positive papillary), WRO (BRAF negative papillary), and FRO (follicular) cells treated with 150 microM seleno-l-methionine (SM) were assessed for viability at 24, 48, and 72 h. Treated FRO cells were examined for cell cycle using flow cytometry, for apoptosis using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, and for gene expression using microarray. Genes identified as upregulated were confirmed by real-time PCR (RT-PCR) and proteins by Western blot analysis. SM treatment significantly decreased the proliferation of all cell lines. TUNEL assay showed no evidence of apoptosis, and flow cytometry showed a significant cell-cycle arrest in S (271% increase, P = 0.006) and G2/M (61% increase, P = 0.002) compared to control. Microarray revealed 21 differentially expressed genes with greater than twofold change. A relative overexpression of growth arrest and DNA damage inducible (GADD)34 and GADD153 in treated cells was confirmed with RT-PCR and Western blot. SM inhibits thyroid cancer cell proliferation through a time dependent upregulation of the GADD family of genes and arrest in S and G2/M phases of the cell cycle. This is the first report of selenium induced inhibition of thyroid cancer cell growth.
authors.affiliation: Weill Medical College of Cornell University, New York, New York 10021, USA. mek2002@med.cornell.edu
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Kato
authors.forename: David J
authors.initials: DJ
authors.lastname: Finley
authors.forename: Carrie C
authors.initials: CC
authors.lastname: Lubitz
authors.forename: Baixin
authors.initials: B
authors.lastname: Zhu
authors.forename: Tracy-Ann
authors.initials: TA
authors.lastname: Moo
authors.forename: Michael R
authors.initials: MR
authors.lastname: Loeven
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Ricci
authors.forename: Rasa
authors.initials: R
authors.lastname: Zarnegar
authors.forename: Meena
authors.initials: M
authors.lastname: Katdare
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Fahey
mesh_terms: D000943:Antigens, Differentiation / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics; D066246:ErbB Receptors / Q000032:analysis / Q000235:genetics; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D020287:In Situ Nick-End Labeling; D046228:Microarray Analysis; D054645:Protein Phosphatase 1; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012643:Selenium / Q000494:pharmacology*; D012645:Selenomethionine / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000737:chemistry / Q000473:pathology*; D051742:Transcription Factor CHOP / Q000032:analysis / Q000235:genetics*
chemical_list: D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; C497249:DDIT3 protein, human; D012333:RNA, Messenger; D051742:Transcription Factor CHOP; D012645:Selenomethionine; D066246:ErbB Receptors; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1; D012643:Selenium