Next Article in Journal
Neoadjuvant Chemoradiotherapy Followed by Esophagectomy with Three-Field Lymph Node Dissection for Thoracic Esophageal Squamous Cell Carcinoma Patients with Clinical Stage III and with Supraclavicular Lymph Node Metastasis
Next Article in Special Issue
Suppressive Effect and Molecular Mechanism of Houttuynia cordata Thunb. Extract against Prostate Carcinogenesis and Castration-Resistant Prostate Cancer
Previous Article in Journal
Novel CD37, Humanized CD37 and Bi-Specific Humanized CD37-CD19 CAR-T Cells Specifically Target Lymphoma
Article

Rabdosianone I, a Bitter Diterpene from an Oriental Herb, Suppresses Thymidylate Synthase Expression by Directly Binding to ANT2 and PHB2

1
Department of Molecular-Targeting Prevention, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
2
Department of Food Science and Human Nutrition, Baika Women’s University, Osaka 567-8578, Japan
3
Artificial Intelligence Research Center, National Institute of Advanced Industrial Science and Technology (AIST), Tokyo 135-0064, Japan
4
Drug Discovery Center, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
5
Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
6
Epidemiology and Prevention Division, Center for Public Health Sciences, National Cancer Center, Tokyo 104-0045, Japan
*
Author to whom correspondence should be addressed.
Academic Editor: Sanjiv Prashar
Cancers 2021, 13(5), 982; https://doi.org/10.3390/cancers13050982
Received: 23 January 2021 / Revised: 19 February 2021 / Accepted: 23 February 2021 / Published: 26 February 2021
(This article belongs to the Special Issue Actual Preventive Drugs and Food Factors on Cancer)
In the present study, we found the novel pleiotropic regulation of the oncogene product thymidylate synthase (TS) by a chemical biology approach to identify rabdosianone I-binding proteins. Rabdosianone I, which is extracted from a traditional Asian herb Isodon japonicus Hara for longevity, suppressed TS expression at mRNA and protein levels. We immobilized rabdosianone I onto nano-magnetic beads and identified two mitochondrial proteins, adenine nucleotide translocase 2 (ANT2) and prohibitin 2 (PHB2), as the direct targets of rabdosianone I in cancer cells. Mechanistically, the knockdown of ANT2 or PHB2 promoted proteasomal degradation of the TS protein. In addition, PHB2 reduced TS mRNA levels. Thus, we provide previously unknown mechanisms of TS regulation by ANT2 and PHB2 and propose the possibility of rabdosianone I as a promising lead compound for the discovery of a novel TS suppressor.
Natural products have numerous bioactivities and are expected to be a resource for potent drugs. However, their direct targets in cells often remain unclear. We found that rabdosianone I, which is a bitter diterpene from an oriental herb for longevity, Isodon japonicus Hara, markedly inhibited the growth of human colorectal cancer cells by downregulating the expression of thymidylate synthase (TS). Next, using rabdosianone I-immobilized nano-magnetic beads, we identified two mitochondrial inner membrane proteins, adenine nucleotide translocase 2 (ANT2) and prohibitin 2 (PHB2), as direct targets of rabdosianone I. Consistent with the action of rabdosianone I, the depletion of ANT2 or PHB2 reduced TS expression in a different manner. The knockdown of ANT2 or PHB2 promoted proteasomal degradation of TS protein, whereas that of not ANT2 but PHB2 reduced TS mRNA levels. Thus, our study reveals the ANT2- and PHB2-mediated pleiotropic regulation of TS expression and demonstrates the possibility of rabdosianone I as a lead compound of TS suppressor. View Full-Text
Keywords: natural products; rabdosianone I; thymidylate synthase; adenine nucleotide translocase 2; prohibitin 2; chemical biology natural products; rabdosianone I; thymidylate synthase; adenine nucleotide translocase 2; prohibitin 2; chemical biology
Show Figures

Figure 1

MDPI and ACS Style

Watanabe, M.; Yamada, Y.; Kurumida, Y.; Kameda, T.; Sukeno, M.; Iizuka-Ohashi, M.; Sowa, Y.; Iizumi, Y.; Takakura, H.; Miyamoto, S.; Sakai, T.; Mutoh, M. Rabdosianone I, a Bitter Diterpene from an Oriental Herb, Suppresses Thymidylate Synthase Expression by Directly Binding to ANT2 and PHB2. Cancers 2021, 13, 982. https://doi.org/10.3390/cancers13050982

AMA Style

Watanabe M, Yamada Y, Kurumida Y, Kameda T, Sukeno M, Iizuka-Ohashi M, Sowa Y, Iizumi Y, Takakura H, Miyamoto S, Sakai T, Mutoh M. Rabdosianone I, a Bitter Diterpene from an Oriental Herb, Suppresses Thymidylate Synthase Expression by Directly Binding to ANT2 and PHB2. Cancers. 2021; 13(5):982. https://doi.org/10.3390/cancers13050982

Chicago/Turabian Style

Watanabe, Motoki, Yasumasa Yamada, Yoichi Kurumida, Tomoshi Kameda, Mamiko Sukeno, Mahiro Iizuka-Ohashi, Yoshihiro Sowa, Yosuke Iizumi, Hideki Takakura, Shingo Miyamoto, Toshiyuki Sakai, and Michihiro Mutoh. 2021. "Rabdosianone I, a Bitter Diterpene from an Oriental Herb, Suppresses Thymidylate Synthase Expression by Directly Binding to ANT2 and PHB2" Cancers 13, no. 5: 982. https://doi.org/10.3390/cancers13050982

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop