Protein kinase A inhibition facilitates the antitumor activity of xanthohumol, a valosin-containing protein inhibitor

Yuki Shikata; Tetsuro Yoshimaru; Masato Komatsu; Hiroto Katoh; Reiko Sato; Shuhei Kanagaki; Yasumasa Okazaki; Shinya Toyokuni; Etsu Tashiro; Shumpei Ishikawa; Toyomasa Katagiri; Masaya Imoto

doi:10.1111/cas.13175

Protein kinase A inhibition facilitates the antitumor activity of xanthohumol, a valosin-containing protein inhibitor

Cancer Sci. 2017 Apr;108(4):785-794. doi: 10.1111/cas.13175. Epub 2017 Apr 20.

Authors

Affiliations

¹ Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.
² Division of Genome Medicine, Institute for Genome Research, Tokushima University, Tokushima, Japan.
³ Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
⁴ JST, PRESTO, Saitama, Japan.
⁵ Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.

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.

Keywords: Adenylate cyclase; antitumor activity; apoptosis; valosin-containing protein; xanthohumol.

MeSH terms

A549 Cells
Adenosine Triphosphatases / metabolism
Adenylyl Cyclases / genetics
Adenylyl Cyclases / metabolism
Animals
Apoptosis / drug effects
Apoptosis / genetics
Blotting, Western
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Proliferation / genetics
Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors*
Cyclic AMP-Dependent Protein Kinases / metabolism
Female
Flavonoids / pharmacology*
HCT116 Cells
HT29 Cells
HeLa Cells
Humans
Inhibitor of Apoptosis Proteins / genetics
Inhibitor of Apoptosis Proteins / metabolism
Intracellular Signaling Peptides and Proteins / pharmacology*
MCF-7 Cells
Mice, Inbred BALB C
Mice, Nude
Neoplasms / drug therapy*
Neoplasms / genetics
Neoplasms / metabolism
Propiophenones / pharmacology*
RNA Interference
Signal Transduction / drug effects
Signal Transduction / genetics
Survivin
Valosin Containing Protein
Xenograft Model Antitumor Assays*

Substances

BIRC5 protein, human
Cell Cycle Proteins
Flavonoids
Inhibitor of Apoptosis Proteins
Intracellular Signaling Peptides and Proteins
Propiophenones
Survivin
protein kinase modulator
Cyclic AMP-Dependent Protein Kinases
Adenosine Triphosphatases
VCP protein, human
Valosin Containing Protein
Vcp protein, mouse
Adenylyl Cyclases
xanthohumol

Associated data

GENBANK/ab16667