Vesnarinone Suppresses TNFα mRNA Expression by Inhibiting Valosin-Containing Protein

• Published in: Molecular pharmacology 2013-05, Vol.83 (5), p.930-938
• Main Authors: Hotta, Kentaro, Nashimoto, Akihiro, Yasumura, Eiji, Suzuki, Masafumi, Azuma, Motoki, Iizumi, Yosuke, Shima, Daisuke, Nabeshima, Ryusuke, Hiramoto, Masaki, Okada, Akira, Sakata-Sogawa, Kumiko, Tokunaga, Makio, Ito, Takumi, Ando, Hideki, Sakamoto, Satoshi, Kabe, Yasuaki, Aizawa, Shinichi, Imai, Takeshi, Yamaguchi, Yuki, Watanabe, Hajime, Handa, Hiroshi
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases - antagonists & inhibitors; Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line; HEK293 Cells; Humans; I-kappa B Proteins - genetics; I-kappa B Proteins - metabolism; NF-kappa B - genetics; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; Quinolines - pharmacology; RNA, Messenger - antagonists & inhibitors; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Valosin Containing Protein
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.112.081935

Vesnarinone is a synthetic quinolinone derivative used in the treatment of cardiac failure and cancer. It is also known to cause agranulocytosis as a side effect, which restricts its use, although the mechanism underlying agranulocytosis is not well understood. Here, we show that vesnarinone binds to valosin-containing protein (VCP), which interacts with polyubiquitinated proteins and is essential for the degradation of IκBα to activate nuclear factor (NF)κB. We show that vesnarinone impairs the degradation of IκBα, and that the impairment of the degradation of IκBα is the result of the inhibition of the interaction between VCP and the 26S proteasome by vesnarinone. These results suggest that vesnarinone suppresses NFκB activation by inhibiting the VCP-dependent degradation of polyubiquitinated IκBα, resulting in the suppression of tumor necrosis factor-α mRNA expression.