title: Glucose-regulated protein 78 is a novel contributor to acquisition of resistance to sorafenib in hepatocellular carcinoma.
abstract: BACKGROUND
  Sorafenib is a newly established cancer drug found to be an effective systemic treatment for advanced hepatocellular carcinoma (HCC). However, little is known about any potential effectors that modify tumor cell sensitivity towards sorafenib. Here, we present the first evidence that glucose-regulated protein 78 (GRP78) is intimately associated with acquisition of resistance towards sorafenib.
  
  
  METHODS
  The role of GRP78 in acquisition of resistance towards sorafenib was determined using HepJ5 (a GRP78-overexpressing subline) and HepG2 as its pair-matched control. RNA interference in cancer cells was applied to determine the influence of GRP78 expression on sensitivity to sorafenib treatment.
  
  
  RESULTS
  We found that HepG2 cells exhibited higher sensitivity toward sorafenib, with 50% inhibition concentration (IC(50)) >20 microMu for HepJ5 and 4.8 microM for HepG2. Specifically, when HepG2 cells received 20 microM sorafenib treatment for 24 h, over 80% of cells underwent apoptosis compared with only 32% of HepJ5 cells under similar experimental conditions. Similarly, GRP78 knockdown in HepJ5 cells by small interfering RNA (siRNA) technique enhanced the efficacy of sorafenib-mediated cell death. This was reflected by a shift of IC(50) values from >20 microM to 4.8 microM.
  
  
  CONCLUSIONS
  GRP78 is a positive modifier for sorafenib resistance acquisition in HCC and represents a prime target for overcoming sorafenib resistance.
authors.affiliation: Department of Radiation Oncology, Taipei Medical University and Hospital, Taipei, Taiwan.
authors.forename: Jeng-Fong
authors.initials: JF
authors.lastname: Chiou
authors.forename: Cheng-Jeng
authors.initials: CJ
authors.lastname: Tai
authors.forename: Ming-Te
authors.initials: MT
authors.lastname: Huang
authors.forename: Po-Li
authors.initials: PL
authors.lastname: Wei
authors.forename: Yu-Huei
authors.initials: YH
authors.lastname: Wang
authors.forename: Jane
authors.initials: J
authors.lastname: An
authors.forename: Chih-Hsiung
authors.initials: CH
authors.lastname: Wu
authors.forename: Tsan-Zon
authors.initials: TZ
authors.lastname: Liu
authors.forename: Yu-Jia
authors.initials: YJ
authors.lastname: Chang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001557:Benzenesulfonates / Q000494:pharmacology*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D000091342:Endoplasmic Reticulum Chaperone BiP; D005434:Flow Cytometry; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D000077157:Sorafenib; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D010671:Phenylurea Compounds; D011725:Pyridines; D034741:RNA, Small Interfering; D009536:Niacinamide; D045304:Cytochromes c; D000077157:Sorafenib; D020169:Caspases