Auraptene Enhances AMP-Activated Protein Kinase Phosphorylation and Thereby Inhibits the Proliferation, Migration and Expression of Androgen Receptors and Prostate-Specific Antigens in Prostate Cancer Cells.
Yasuyuki Akasaka: Department of Biomedical Chemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
Shun Hasei: Department of Biomedical Chemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
Yukino Ohata: Department of Biomedical Chemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
Machi Kanna: Department of Biomedical Chemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
Yusuke Nakatsu: Department of Biomedical Chemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
Hideyuki Sakoda: Department of Bioregulatory Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
Midori Fujishiro: Division of Diabetes and Metabolic Diseases, Nihon University School of Medicine, Tokyo 173-8610, Japan.
Akifumi Kushiyama: Department of Pharmacotherapy, Meiji Pharmaceutical University, Kiyose 204-8588, Japan. ORCID
Hiraku Ono: Department of Clinical Cell Biology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
Akio Matsubara: Department of Urology, JA Hiroshima General Hospital, Hatsukaichi 738-8503, Japan.
Nobuyuki Hinata: Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan. ORCID
Tomoichiro Asano: Department of Biomedical Chemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
Takeshi Yamamotoya: Department of Biomedical Chemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan.
extract reportedly activates AMPK. Because this extract contains an abundance of auraptene, we investigated whether pure auraptene activates AMPK and inhibits proliferation using prostate cancer cell lines. Indeed, auraptene inhibited the proliferation and migration of LNCaP cells and induced phosphorylation of AMPK or its downstream ACC in LNCaP, PC3, and HEK-293 cells, but not in DU145 cells not expressing LKB1. In addition, the mTOR-S6K pathway, located downstream from activated AMPK, was also markedly suppressed by auraptene treatment. Importantly, it was shown that auraptene reduced androgen receptor (AR) and prostate-specific antigen (PSA) expressions at both the protein and the mRNA level. This auraptene-induced downregulation of PSA was partially but significantly reversed by treatment with AMPK siRNA or the AMPK inhibitor compound C, suggesting AMPK activation to, at least partially, be causative. Finally, in DU145 cells lacking the LKB1 gene, exogenously induced LKB1 expression restored AMPK phosphorylation by auraptene, indicating the essential role of LKB1. In summary, auraptene is a potent AMPK activator that acts by elevating the AMP/ATP ratio, thereby potentially suppressing prostate cancer progression, via at least three molecular mechanisms, including suppression of the mTOR-S6K pathway, reduced lipid synthesis, and AR downregulation caused by AMPK activation.
