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Luteolin sensitizes human 786-O renal cell carcinoma cells to TRAIL-induced apoptosis

Authors
  • Ou, Yen-Chuan
  • Li, Jian-Ri
  • Kuan, Yu-Hsiang
  • Raung, Shue-Ling
  • Wang, Chung-Chiang
  • Hung, Yu-Yeh
  • Pan, Pin-Ho
  • Lu, Hsi-Chi
  • Chen, Chun-Jung1, 2, 3, 4, 5, 6, 2, 7, 8, 9, 10, 11, 10, 12, 13, 14, 13
  • 1 Division of Urology
  • 2 Taichung Veterans General Hospital
  • 3 Department of Pharmacology
  • 4 School of Medicine
  • 5 Chung Shan Medical University
  • 6 Department of Education and Research
  • 7 Department of Pediatrics
  • 8 Tungs' Taichung MetroHarbor Hospital
  • 9 Food Science Department and Graduate Institute
  • 10 Tunghai University
  • 11 Center for General Education
  • 12 Institute of Biomedical Sciences
  • 13 National Chung Hsing University
  • 14 Rong Hsing Research Center for Translational Medicine
Type
Published Article
Journal
Life Sciences
Publisher
Elsevier
Publication Date
Jan 01, 2014
Accepted Date
Feb 01, 2014
Volume
100
Issue
2
Pages
110–117
Identifiers
DOI: 10.1016/j.lfs.2014.02.002
Source
Elsevier
Keywords
License
Unknown

Abstract

AimsTumor 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. Main methodsThe 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. Key findingsWe 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. SignificanceData 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.

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