title: TWEAK/Fn14 signaling mediates gastric cancer cell resistance to 5-fluorouracil via NF-κB activation.
abstract: Chemoresistance is one of the most serious problems in the treatment of cancer. In the present study, we show that Fn14 promotes resistance to 5-fluorouracil (5-FU) in gastric cancer (GC). We found that 5-FU treatment upregulated Fn14 expression in various cancer cell lines, including GC cell lines, and that knockdown of Fn14 using shRNA accelerated 5-FU sensitivity. In contrast, Fn14 overexpression or TWEAK treatment promoted resistance to 5-FU. Furthermore, we investigated the mechanisms underlying Fn14-mediated chemoresistance. We first revealed that 5-FU-mediated upregulation of Fn14 occurred as a result of NF-κB activation, indicating that 5-FU-mediated NF-κB activation was the principal event underlying Fn14 upregulation and 5-FU resistance in GC. Taken together, our results suggest that Fn14 is a novel therapeutic target and that inhibition of Fn14 combined with 5-FU treatment may be an effective molecular therapeutic strategy to treat 5-FU-resistant gastric cancers.
authors: Medical Genomics Research Center, KRIBB, Daejeon 305-806, Republic of Korea.
authors: Oh-Hyung
authors: OH
authors: Kwon
authors: Medical Genomics Research Center, KRIBB, Daejeon 305-806, Republic of Korea.
authors: Jong Hwan
authors: JH
authors: Kim
authors: Medical Genomics Research Center, KRIBB, Daejeon 305-806, Republic of Korea.
authors: Seon-Young
authors: SY
authors: Kim
authors: Medical Genomics Research Center, KRIBB, Daejeon 305-806, Republic of Korea.
authors: Yong Sung
authors: YS
authors: Kim
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D000074049:Cytokine TWEAK; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000074050:TWEAK Receptor; D014407:Tumor Cells, Cultured; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000964:Antimetabolites, Antineoplastic; D000074049:Cytokine TWEAK; D016328:NF-kappa B; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors; D005472:Fluorouracil