BACKGROUND: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a novel member of the tumor necrosis factor family, induces apoptosis in TRAIL-sensitive tumors through the activation of the caspase pathway. Sodium butyrate (NaBT) induces differentiation and apoptosis in certain colorectal cancers; the molecular mechanisms for these effects have not been clearly defined. The purpose of our study was to determine whether NaBT sensitizes TRAIL-resistant human colon cancer cells to the effects of TRAIL. METHODS: Human colon cancer cells (KM12C, KML4A, and KM20) that are resistant to TRAIL treatment alone were treated with TRAIL (100 ng/mL), NaBT (5 mmol/L), or a combination of these agents and harvested for total RNA and protein. Western blots were performed to assess intracellular expression of Flice-like inhibitory protein (FLIP), a caspase inhibitor. Percent-specific apoptosis, relative caspase-3 activity, and Annexin-V immunofluorescence were determined at 24 and 48 hours. Cell cycle--related gene expression was assessed by RNase protection. RESULTS: Treatment with NaBT for 24 and 48 hours decreased FLIP protein expression in all cell lines. Furthermore, NaBT sensitized these resistant cancer cells to the effects of TRAIL with significant increases noted in cell death, caspase-3 activity, and Annexin-V staining compared with NaBT alone. CONCLUSIONS: Our findings suggest that the reduction of FLIP protein levels by NaBT renders TRAIL-resistant human colon cancer cells sensitive to TRAIL-mediated apoptosis. The combination of TRAIL with agents (such as NaBT, which target proteins that prevent cell death) may provide a more effective and less toxic regimen for the treatment of resistant colon cancers.
BACKGROUND:Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a novel member of the tumor necrosis factor family, induces apoptosis in TRAIL-sensitive tumors through the activation of the caspase pathway. Sodium butyrate (NaBT) induces differentiation and apoptosis in certain colorectal cancers; the molecular mechanisms for these effects have not been clearly defined. The purpose of our study was to determine whether NaBT sensitizes TRAIL-resistant humancolon cancer cells to the effects of TRAIL. METHODS:Humancolon cancer cells (KM12C, KML4A, and KM20) that are resistant to TRAIL treatment alone were treated with TRAIL (100 ng/mL), NaBT (5 mmol/L), or a combination of these agents and harvested for total RNA and protein. Western blots were performed to assess intracellular expression of Flice-like inhibitory protein (FLIP), a caspase inhibitor. Percent-specific apoptosis, relative caspase-3 activity, and Annexin-V immunofluorescence were determined at 24 and 48 hours. Cell cycle--related gene expression was assessed by RNase protection. RESULTS: Treatment with NaBT for 24 and 48 hours decreased FLIP protein expression in all cell lines. Furthermore, NaBT sensitized these resistant cancer cells to the effects of TRAIL with significant increases noted in cell death, caspase-3 activity, and Annexin-V staining compared with NaBT alone. CONCLUSIONS: Our findings suggest that the reduction of FLIP protein levels by NaBT renders TRAIL-resistant humancolon cancer cells sensitive to TRAIL-mediated apoptosis. The combination of TRAIL with agents (such as NaBT, which target proteins that prevent cell death) may provide a more effective and less toxic regimen for the treatment of resistant colon cancers.
Authors: Anderly C Chüeh; Janson W T Tse; Michael Dickinson; Paul Ioannidis; Laura Jenkins; Lars Togel; BeeShin Tan; Ian Luk; Mercedes Davalos-Salas; Rebecca Nightingale; Matthew R Thompson; Bryan R G Williams; Guillaume Lessene; Erinna F Lee; Walter D Fairlie; Amardeep S Dhillon; John M Mariadason Journal: Clin Cancer Res Date: 2017-06-13 Impact factor: 12.531
Authors: David M Lucas; Lapo Alinari; Derek A West; Melanie E Davis; Ryan B Edwards; Amy J Johnson; Kristie A Blum; Craig C Hofmeister; Michael A Freitas; Mark R Parthun; Dasheng Wang; Amy Lehman; Xiaoli Zhang; David Jarjoura; Samuel K Kulp; Carlo M Croce; Michael R Grever; Ching-Shih Chen; Robert A Baiocchi; John C Byrd Journal: PLoS One Date: 2010-06-03 Impact factor: 3.240
Authors: Ville Hietakangas; Minna Poukkula; Kaisa M Heiskanen; Jarkko T Karvinen; Lea Sistonen; John E Eriksson Journal: Mol Cell Biol Date: 2003-02 Impact factor: 4.272
Authors: Andrew J Wilson; Anderly C Chueh; Lars Tögel; Georgia A Corner; Naseem Ahmed; Sanjay Goel; Do-Sun Byun; Shannon Nasser; Michele A Houston; Minaxi Jhawer; Helena J M Smartt; Lucas B Murray; Courtney Nicholas; Barbara G Heerdt; Diego Arango; Leonard H Augenlicht; John M Mariadason Journal: Cancer Res Date: 2010-01-12 Impact factor: 12.701