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
<i>Citrus hassaku</i> 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...
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| Format: | Article |
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MDPI AG
2023-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/21/16011 |
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| author | Yasuyuki Akasaka Shun Hasei Yukino Ohata Machi Kanna Yusuke Nakatsu Hideyuki Sakoda Midori Fujishiro Akifumi Kushiyama Hiraku Ono Akio Matsubara Nobuyuki Hinata Tomoichiro Asano Takeshi Yamamotoya |
| author_facet | Yasuyuki Akasaka Shun Hasei Yukino Ohata Machi Kanna Yusuke Nakatsu Hideyuki Sakoda Midori Fujishiro Akifumi Kushiyama Hiraku Ono Akio Matsubara Nobuyuki Hinata Tomoichiro Asano Takeshi Yamamotoya |
| author_sort | Yasuyuki Akasaka |
| collection | DOAJ |
| description | <i>Citrus hassaku</i> 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. |
| first_indexed | 2024-03-11T11:27:11Z |
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| id | doaj.art-44ff9359f15b4ceea2ed36afec31aca0 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T11:27:11Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-44ff9359f15b4ceea2ed36afec31aca02023-11-10T15:06:07ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-11-0124211601110.3390/ijms242116011Auraptene Enhances AMP-Activated Protein Kinase Phosphorylation and Thereby Inhibits the Proliferation, Migration and Expression of Androgen Receptors and Prostate-Specific Antigens in Prostate Cancer CellsYasuyuki Akasaka0Shun Hasei1Yukino Ohata2Machi Kanna3Yusuke Nakatsu4Hideyuki Sakoda5Midori Fujishiro6Akifumi Kushiyama7Hiraku Ono8Akio Matsubara9Nobuyuki Hinata10Tomoichiro Asano11Takeshi Yamamotoya12Department of Biomedical Chemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, JapanDepartment of Biomedical Chemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, JapanDepartment of Biomedical Chemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, JapanDepartment of Biomedical Chemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, JapanDepartment of Biomedical Chemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, JapanDepartment of Bioregulatory Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, JapanDivision of Diabetes and Metabolic Diseases, Nihon University School of Medicine, Tokyo 173-8610, JapanDepartment of Pharmacotherapy, Meiji Pharmaceutical University, Kiyose 204-8588, JapanDepartment of Clinical Cell Biology, Graduate School of Medicine, Chiba University, Chiba 260-8670, JapanDepartment of Urology, JA Hiroshima General Hospital, Hatsukaichi 738-8503, JapanDepartment of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, JapanDepartment of Biomedical Chemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, JapanDepartment of Biomedical Chemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan<i>Citrus hassaku</i> 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.https://www.mdpi.com/1422-0067/24/21/16011aurapteneAMPKLKB1prostate cancerandrogen receptorprostate-specific antigen |
| spellingShingle | Yasuyuki Akasaka Shun Hasei Yukino Ohata Machi Kanna Yusuke Nakatsu Hideyuki Sakoda Midori Fujishiro Akifumi Kushiyama Hiraku Ono Akio Matsubara Nobuyuki Hinata Tomoichiro Asano Takeshi Yamamotoya 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 International Journal of Molecular Sciences auraptene AMPK LKB1 prostate cancer androgen receptor prostate-specific antigen |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | auraptene AMPK LKB1 prostate cancer androgen receptor prostate-specific antigen |
| url | https://www.mdpi.com/1422-0067/24/21/16011 |
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