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

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)574-579
Number of pages6
JournalChemistryOpen
Volume5
Issue number6
DOIs
Publication statusPublished - 2016 Dec 1

Keywords

  • TRAIL resistance
  • endoplasmic reticulum stress
  • natural products
  • target identification
  • valosin-containing protein

ASJC Scopus subject areas

  • Chemistry(all)

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    Arai, M. A., Taguchi, S., Komatsuzaki, K., Uchiyama, K., Masuda, A., Sampei, M., Satoh, M., Kado, S., & Ishibashi, M. (2016). Valosin-containing Protein is a Target of 5′-l Fuligocandin B and Enhances TRAIL Resistance in Cancer Cells. ChemistryOpen, 5(6), 574-579. https://doi.org/10.1002/open.201600081