TWEAK/Fn14 signaling mediates gastric cancer cell resistance to 5-fluorouracil via NF-κB activation

Kwon,Oh-Hyung; Kim,Jong Hwan; Kim,Seon-Young; Kim,Yong Sung

doi:10.3892/ijo.2013.2211

TWEAK/Fn14 signaling mediates gastric cancer cell resistance to 5-fluorouracil via NF-κB activation

Authors:
- Oh-Hyung Kwon
- Jong Hwan Kim
- Seon-Young Kim
- Yong Sung Kim
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Affiliations: Medical Genomics Research Center, KRIBB, Daejeon 305-806, Republic of Korea
Published online on: December 9, 2013 https://doi.org/10.3892/ijo.2013.2211
Pages: 583-590

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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.

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