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

Int J Oncol. 2014 Feb;44(2):583-90. doi: 10.3892/ijo.2013.2211. Epub 2013 Dec 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimetabolites, Antineoplastic / pharmacology
  • Apoptosis / drug effects
  • Blotting, Western
  • Cell Proliferation / drug effects
  • Cytokine TWEAK
  • Drug Resistance, Neoplasm*
  • Fluorouracil / pharmacology*
  • Humans
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, Tumor Necrosis Factor / antagonists & inhibitors
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / pathology
  • TWEAK Receptor
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor Inhibitors
  • Tumor Necrosis Factors / genetics
  • Tumor Necrosis Factors / metabolism*

Substances

  • Antimetabolites, Antineoplastic
  • Cytokine TWEAK
  • NF-kappa B
  • RNA, Messenger
  • RNA, Small Interfering
  • Receptors, Tumor Necrosis Factor
  • TNFRSF12A protein, human
  • TNFSF12 protein, human
  • TWEAK Receptor
  • Tumor Necrosis Factor Inhibitors
  • Tumor Necrosis Factors
  • Fluorouracil