title: Luteolin sensitizes human 786-O renal cell carcinoma cells to TRAIL-induced apoptosis.
abstract: OBJECTIVE
  Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been considered to be one of the most promising candidates in research on treatments for cancer, including renal cell carcinoma (RCC). However, many cells are resistant to TRAIL-induced apoptosis which limits the potential application of TRAIL in cancer therapy. Luteolin, a naturally occurring flavonoid, has been identified as a potential therapeutic and preventive agent for cancer because of its potent cancer cell-killing activity. In this study, we investigated whether luteolin treatment could modulate TRAIL-induced apoptosis in RCC.
  
  
  METHODS
  The effect of luteolin on TRAIL sensitivity was assessed in human RCC 786-O, ACHN, and A498 cells. The underlying regulatory cascades were approached by biochemical and pharmacological strategies.
  
  
  RESULTS
  We found that nontoxic concentration of luteolin alone had no effect on the level of apoptosis, but a combination treatment of TRAIL and luteolin caused significant extrinsic and intrinsic apoptosis. The sensitization was accompanied by Bid cleavage, Mcl-1 and FLIP down-regulation, DR4/DR5 protein expression and cell surface presentation, and Akt and signal transducer and activator of transcription-3 (STAT3) inactivation. Among these phenomena, changes in FLIP, Akt, and, STAT3 are more prone to the effects of luteolin treatment. Studies have further demonstrated that inactivation of Akt or STAT3 alone was sufficient to down-regulate FLIP expression and sensitized 786-O cells to TRAIL-induced apoptosis.
  
  
  CONCLUSIONS
  Data from this study thus provide in vitro evidence supporting the notion that luteolin is a potential sensitizer of TRAIL in anticancer therapy against human RCC involving Akt and STAT3 inactivation.
authors: Division of Urology, Taichung Veterans General Hospital, Taichung, Taiwan.
authors: Yen-Chuan
authors: YC
authors: Ou
authors: Division of Urology, Taichung Veterans General Hospital, Taichung, Taiwan.
authors: Jian-Ri
authors: JR
authors: Li
authors: Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors: Yu-Hsiang
authors: YH
authors: Kuan
authors: Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan.
authors: Shue-Ling
authors: SL
authors: Raung
authors: Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan.
authors: Chung-Chiang
authors: CC
authors: Wang
authors: Division of Urology, Taichung Veterans General Hospital, Taichung, Taiwan.
authors: Yu-Yeh
authors: YY
authors: Hung
authors: Department of Pediatrics, Tungs' Taichung MetroHarbor Hospital, Taichung, Taiwan.
authors: Pin-Ho
authors: PH
authors: Pan
authors: Food Science Department and Graduate Institute, Tunghai University, Taichung, Taiwan.
authors: Hsi-Chi
authors: HC
authors: Lu
authors: Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan; Center for General Education, Tunghai University, Taichung, Taiwan; Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan; Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan. Electronic address: cjchen@vghtc.gov.tw.
authors: Chun-Jung
authors: CJ
authors: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D047311:Luteolin / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D051017:Apoptosis Regulatory Proteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051057:Proto-Oncogene Proteins c-akt; D047311:Luteolin
keywords: FLIP; Luteolin; Renal cell carcinoma; TRAIL