title: Modulation of matrix metalloproteinase activity in human thyroid cancer cell lines using demethylating agents and histone deacetylase inhibitors.
abstract: BACKGROUND
  The purpose of this study was to investigate the effects of treating human thyroid cancer cell lines with demethylating agents and histone deacetylase (HDAC) inhibitors to see if they would downregulate expression and activity of the matrix metalloproteinases (MMP)-2 and MMP-9, resulting in inhibition of growth and invasion.
  
  
  METHODS
  A total of 1 papillary cancer cell line (TPC-1) and 3 follicular thyroid cancer cell lines (FTC-133, FTC-236, and FTC-238) were treated with the demethylating agent 5-azacytidine (5-AZC) and the HDAC inhibitors trichostatin A (TSA) and valproic acid (VA). The activity of MMP proteins was determined using gelatin zymography, and commercially available assays were used to quantify growth inhibition and thyroid cancer cell invasion.
  
  
  RESULTS
  Treatment with TSA and VA resulted in decreased protein activity of MMP-2 and MMP-9 in all cell lines in a dose-dependent manner after 48 hours of treatment compared with untreated controls. In addition, 5-, TSA, and VA caused inhibition of growth in the range of 25-80% for all cell lines at 24, 48, and 72 hours. VA and TSA significantly decreased cell invasion in the FTC-133 and TPC-1 cell lines.
  
  
  CONCLUSIONS
  The HDAC inhibitors TSA and VA decreased the protein activity of MMP-2 and MMP-9 and, in combination with the demethylating agent 5-AZC, inhibited cellular growth in human papillary and follicular thyroid cancer cell lines. These results elucidate our understanding of the pathways affected by the demethylating agents and HDAC inhibitors, and provide further evidence that MMPs are a potentially useful target for molecular therapies in patients with aggressive or refractory thyroid cancers.
authors.affiliation: Department of Surgery, University of California, San Francisco, CA, USA. ellmit@yahoo.com
authors.forename: Elliot J
authors.initials: EJ
authors.lastname: Mitmaker
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Griff
authors.forename: Raymon H
authors.initials: RH
authors.lastname: Grogan
authors.forename: Rajabrata
authors.initials: R
authors.lastname: Sarkar
authors.forename: Electron
authors.initials: E
authors.lastname: Kebebew
authors.forename: Quan-Yang
authors.initials: QY
authors.lastname: Duh
authors.forename: Orlo H
authors.initials: OH
authors.lastname: Clark
authors.forename: Wen T
authors.initials: WT
authors.lastname: Shen
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000188:drug therapy* / Q000201:enzymology; D000231:Adenocarcinoma, Papillary / Q000188:drug therapy* / Q000201:enzymology; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001374:Azacitidine / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D014635:Valproic Acid / Q000627:therapeutic use
chemical_list: D000964:Antimetabolites, Antineoplastic; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; C012589:trichostatin A; D014635:Valproic Acid; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D001374:Azacitidine