Valosin-containing Protein is a Target of 5′-l Fuligocandin B and Enhances TRAIL Resistance in Cancer Cells

Midori A. Arai, Shota Taguchi, Kazuhiro Komatsuzaki, Kento Uchiyama, Ayaka Masuda, Mana Sampei, Mamoru Satoh, Sayaka Kado, Masami Ishibashi

研究成果: Article査読

7 被引用数 (Scopus)

抄録

Fuligocandin B (2) is a novel natural product that can overcome TRAIL resistance. We synthesized enatiomerically pure fuligocandin B (2) and its derivative 5′-I fuligocandin B (4), and found that the latter had an improved biological activity against the human gastric cancer cell line, AGS. We attached a biotin linker and photoactivatable aryl diazirine group to 5′-I fuligocandin B (4), and employed a pull-down assay to identify valosin-containing protein (VCP/p97), an AAA ATPase, as a 5′-I fuligocandin B (4) target protein. Knock-down of VCP by siRNA enhanced sensitivity to TRAIL in AGS cells. In addition, 4 enhanced CHOP and DR5 protein expression, and overall intracellular levels of ubiquitinated protein. These data suggest that endoplasmic reticulum stress caused through VCP inhibition by 4 increases CHOP-mediated DR5 up-regulation, which enhances TRAIL-induced cell death in AGS cells. To the best of our knowledge, this is the first example to show a relationship between VCP and TRAIL-resistance-overcoming activity in cancer cells.

本文言語English
ページ(範囲)574-579
ページ数6
ジャーナルChemistryOpen
5
6
DOI
出版ステータスPublished - 2016 12 1
外部発表はい

ASJC Scopus subject areas

  • Chemistry(all)

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