title: Valosin-containing Protein is a Target of 5'-l Fuligocandin B and Enhances TRAIL Resistance in Cancer Cells.
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,4enhanced CHOP and DR5 protein expression, and overall intracellular levels of ubiquitinated protein. These data suggest that endoplasmic reticulum stress caused through VCP inhibition by4increases 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences Chiba University 1-8-1 Inohana, Chuo-ku Chiba 260-8675 Japan.
authors.forename: Midori A
authors.initials: MA
authors.lastname: Arai
authors.affiliation: Graduate School of Pharmaceutical Sciences Chiba University 1-8-1 Inohana, Chuo-ku Chiba 260-8675 Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Taguchi
authors.affiliation: Graduate School of Pharmaceutical Sciences Chiba University 1-8-1 Inohana, Chuo-ku Chiba 260-8675 Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Komatsuzaki
authors.affiliation: Graduate School of Pharmaceutical Sciences Chiba University 1-8-1 Inohana, Chuo-ku Chiba 260-8675 Japan.
authors.forename: Kento
authors.initials: K
authors.lastname: Uchiyama
authors.affiliation: Graduate School of Pharmaceutical Sciences Chiba University 1-8-1 Inohana, Chuo-ku Chiba 260-8675 Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Masuda
authors.affiliation: Graduate School of Pharmaceutical Sciences Chiba University 1-8-1 Inohana, Chuo-ku Chiba 260-8675 Japan.
authors.forename: Mana
authors.initials: M
authors.lastname: Sampei
authors.affiliation: Division of Clinical Mass Spectrometry Chiba University Hospital 1-8-1 Inohana, Chuo-ku Chiba260-8670 Japan; Chemical Analysis Center Chiba University 1-33 Yayoi-cho, Inage-ku Chiba263-8522 Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Satoh
authors.affiliation: Chemical Analysis Center Chiba University 1-33 Yayoi-cho, Inage-ku Chiba 263-8522 Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kado
authors.affiliation: Graduate School of Pharmaceutical Sciences Chiba University 1-8-1 Inohana, Chuo-ku Chiba 260-8675 Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Ishibashi
keywords: TRAIL resistance; endoplasmic reticulum stress; natural products; target identification; valosin-containing protein