title: Proteasome inhibition potentiates the cytotoxic effects of hyperthermia in HT-29 colon cancer cells through inhibition of heat shock protein 27.
abstract: BACKGROUND
  The purpose of this study was to investigate whether proteasome inhibition acts as a thermal sensitizing agent to induce tumor cell death in a colon cancer cell line.
  
  
  METHODS
  HT-29 colon cancer cells were exposed to hyperthermia (43 degrees C) in the presence of proteasome inhibition for 1 h. Viable cell mass and apoptosis were measured by MTT and annexin V staining, respectively. Protein levels were determined by Western blot analysis.
  
  
  RESULTS
  A significant synergistic effect on cell viability with proteasome inhibition was noted under hyperthermic conditions compared to hyperthermia alone (p < 0.05). Increases in phosphorylated ERK and decreases in HSP27 levels were observed in the cells exposed to proteasome inhibition at 43 degrees C. Pretreatment with an inhibitor of ERK yielded an additional increase in apoptosis when used in combination with proteasome inhibition and hyperthermia. Decreased expression of HSP27 by siRNA also resulted in increased thermally induced apoptotic cell death.
  
  
  CONCLUSIONS
  Thermal sensitization through proteasome inhibition may represent a novel approach to increase the efficacy of hyperthermia as an anticancer modality.
authors.affiliation: Division of Surgical Oncology, UMDNJ - New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
authors.forename: Reza
authors.initials: R
authors.lastname: Rezavi
authors.forename: Cha-Chi
authors.initials: CC
authors.lastname: Wang
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Harrison
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism* / Q000628:therapy*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019073:HT29 Cells; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D006979:Hyperthermia, Induced; D007976:Leupeptins / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002070:Butadienes; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; D007976:Leupeptins; D009570:Nitriles; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; C113580:U 0126; C089486:carbobenzoxy-leucyl-leucyl-norvalinal; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde