title: Protein kinase A inhibition facilitates the antitumor activity of xanthohumol, a valosin-containing protein inhibitor.
abstract: Xanthohumol (XN), a simple prenylated chalcone, can be isolated from hops and has the potential to be a cancer chemopreventive agent against several human tumor cell lines. We previously identified valosin-containing protein (VCP) as a target of XN; VCP can also play crucial roles in cancer progression and prognosis. Therefore, we investigated the molecular mechanisms governing the contribution of VCP to the antitumor activity of XN. Several human tumor cell lines were treated with XN to investigate which human tumor cell lines are sensitive to XN. Several cell lines exhibited high sensitivity to XN both in vitro and in vivo. shRNA screening and bioinformatics analysis identified that the inhibition of the adenylate cyclase (AC) pathway synergistically facilitated apoptosis induced by VCP inhibition. These results suggest that there is crosstalk between the AC pathway and VCP function, and targeting both VCP and the AC pathway is a potential chemotherapeutic strategy for a subset of tumor cells.
authors.affiliation: Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.
authors.forename: Yuki
authors.identifier: http://orcid.org/0000-0003-0203-1794
authors.initials: Y
authors.lastname: Shikata
authors.affiliation: Division of Genome Medicine, Institute for Genome Research, Tokushima University, Tokushima, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Yoshimaru
authors.affiliation: Division of Genome Medicine, Institute for Genome Research, Tokushima University, Tokushima, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.|JST, PRESTO, Saitama, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Katoh
authors.affiliation: Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Sato
authors.affiliation: Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Kanagaki
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Okazaki
authors.affiliation: Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors.forename: Shinya
authors.identifier: http://orcid.org/0000-0002-5757-1109
authors.initials: S
authors.lastname: Toyokuni
authors.affiliation: Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.
authors.forename: Etsu
authors.initials: E
authors.lastname: Tashiro
authors.affiliation: Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shumpei
authors.initials: S
authors.lastname: Ishikawa
authors.affiliation: Division of Genome Medicine, Institute for Genome Research, Tokushima University, Tokushima, Japan.
authors.forename: Toyomasa
authors.initials: T
authors.lastname: Katagiri
authors.affiliation: Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.
authors.forename: Masaya
authors.identifier: http://orcid.org/0000-0002-9645-5426
authors.initials: M
authors.lastname: Imoto
mesh_terms: D000072283:A549 Cells; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D045325:HCT116 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011427:Propiophenones / Q000494:pharmacology*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000077022:Survivin; D000074405:Valosin Containing Protein; D023041:Xenograft Model Antitumor Assays
chemical_list: C107489:BIRC5 protein, human; D018797:Cell Cycle Proteins; D005419:Flavonoids; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011427:Propiophenones; D000077022:Survivin; C015482:protein kinase modulator; D017868:Cyclic AMP-Dependent Protein Kinases; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse; D000262:Adenylyl Cyclases; C104536:xanthohumol
keywords: Adenylate cyclase; antitumor activity; apoptosis; valosin-containing protein; xanthohumol