title: Targeting the proteasome as a promising therapeutic strategy in thyroid cancer.
abstract: OBJECTIVE
  Targeting the ubiquitin-proteasome system by using proteasome inhibitors represents a novel approach for cancer therapy. Anaplastic thyroid cancer (ATC), a subtype of thyroid cancer (TC), fails to respond to conventional TC treatment. Here we investigated the effects of bortezomib on TC in vitro. Further, the study aimed to evaluate its potential for TC treatment in vivo.
  
  
  METHODS
  Three anaplastic (Hth74, C643, Kat4), one follicular (FTC133), and one papillary (TPC1) TC cell lines were used. Antiproliferative, proapoptotic, and transcriptional effects of bortezomib treatment were analyzed in vitro and growth inhibition of ATC xenografts in vivo. Tumor samples were analyzed by Ki67, CD31, caspase-3, and NF-κB immunohistochemistry.
  
  
  RESULTS
  In vitro, bortezomib inhibited proliferation of TC cells (IC(50) 4-10 nM), increased caspase-3 activity and induced cell cycle arrest. NF-κB activity was affected differently. In vivo, bortezomib treatment was effective in reducing tumor volume (up to 74%), accompanied by reduced proliferation (Ki67) and 57% reduced tumor vascularity.
  
  
  CONCLUSIONS
  Proteasome inhibition is effective in reducing cell growth and inducing apoptosis of ATC in vitro and inhibiting tumor growth and vascularity in vivo. However, the impact on nuclear transcription remains controversial. Clinical evaluation of bortezomib treatment in ATC is warranted.
authors: Department of Surgery, University Hospital of Giessen and Marburg, Philipps-University of Marburg, Marburg, Germany.
authors: Annette
authors: A
authors: Wunderlich
authors: Tjadina
authors: T
authors: Arndt
authors: Melina
authors: M
authors: Fischer
authors: Silvia
authors: S
authors: Roth
authors: Annette
authors: A
authors: Ramaswamy
authors: Brandon H
authors: BH
authors: Greene
authors: Cornelia
authors: C
authors: Brendel
authors: Ulrike
authors: U
authors: Hinterseher
authors: Detlef K
authors: DK
authors: Bartsch
authors: Sebastian
authors: S
authors: Hoffmann
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002291:Carcinoma, Papillary / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D001897:Boronic Acids; D016328:NF-kappa B; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex