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