title: Sorafenib enhances radiation-induced apoptosis in hepatocellular carcinoma by inhibiting STAT3.
abstract: OBJECTIVE
  Hepatocellular carcinoma (HCC) is one of the most common and lethal human malignancies. Lack of efficient therapy for advanced HCC is a pressing problem worldwide. This study aimed to determine the efficacy and mechanism of combined sorafenib and radiation therapy treatment for HCC.
  
  
  METHODS
  HCC cell lines (PLC5, Huh-7, Sk-Hep1, and Hep3B) were treated with sorafenib, radiation, or both, and apoptosis and signal transduction were analyzed.
  
  
  RESULTS
  All 4 HCC cell lines showed resistance to radiation-induced apoptosis; however, this resistance could be reversed in the presence of sorafenib. Inhibition of phospho-STAT3 was found in cells treated with sorafenib or sorafenib plus radiation and subsequently reduced the expression levels of STAT3-related proteins, Mcl-1, cyclin D1, and survivin. Silencing STAT3 by RNA interference overcame apoptotic resistance to radiation in HCC cells, and the ectopic expression of STAT3 in HCC cells abolished the radiosensitizing effect of sorafenib. Moreover, sorafenib plus radiation significantly suppressed PLC5 xenograft tumor growth.
  
  
  CONCLUSIONS
  These results indicate that sorafenib sensitizes resistant HCC cells to radiation-induced apoptosis via downregulating phosphorylation of STAT3 in vitro and in vivo.
authors.affiliation: Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Chao-Yuan
authors.initials: CY
authors.lastname: Huang
authors.forename: Chen-Si
authors.initials: CS
authors.lastname: Lin
authors.forename: Wei-Tien
authors.initials: WT
authors.lastname: Tai
authors.forename: Chi-Ying
authors.initials: CY
authors.lastname: Hsieh
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000628:therapy*; D059248:Chemoradiotherapy / Q000379:methods; D019938:Cyclin D1 / Q000037:antagonists & inhibitors; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors; D008113:Liver Neoplasms / Q000628:therapy*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D034622:RNA Interference; D011836:Radiation Tolerance / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D000077157:Sorafenib; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D050796:STAT3 Transcription Factor; D000077022:Survivin; D019938:Cyclin D1; D009536:Niacinamide; D000077157:Sorafenib