Analysis of antitumor effect mechanism by dopamine signal inhibitor

• Project/Area Number: 18K15223
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Tokyo University of Science
• Principal Investigator: Okazaki Shogo 東京理科大学, 研究推進機構生命医科学研究所, 助教 (20784044)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 悪性腫瘍 / ドパミン / セロトニン / 口腔扁平上皮癌 / 酸化ストレス / 代謝

Outline of Final Research Achievements

In this study, I analyzed anti-tumor mechanism of dopamine signal inhibitors. I found that dopamine receptor antagonist induces accumulation of hydrogen peroxide in tumor cells.
This mechanism contributes to anti-tumor effect of dopamine receptor antagonist. Furthermore, I identified that antagonistic effect against serotonin receptors may also contributes to antitumor effect of dopamine receptor antagonist. This study revealed potential of dopamine/serotonin signal as novel tumor therapy target.

Academic Significance and Societal Importance of the Research Achievements

がん細胞における治療抵抗性は、臨床上の最も深刻な課題の一つである。本研究では、治療抵抗性癌細胞に対してドパミン受容体に対するアンタゴニストが抗腫瘍効果を示すという結果に基づき、腫瘍細胞におけるドパミン受容体の機能解析及びその抗腫瘍効果機序の解析を行った。その結果、ドパミン受容体アンタゴニストによる抗腫瘍効果機序の一端を明らかとし、また、ある種のセロトニン受容体についても悪性腫瘍の進展に寄与している可能性を見出した。この研究成果により、ドパミンおよびセロトニン受容体を標的とすることで新たな癌治療の開発への発展の可能性を示すことができた。

Research Products

• [Journal Article] Vasodilator oxyfedrine inhibits aldehyde metabolism and thereby sensitizes cancer cells to xCT-targeted therapy. (2020)
  • Author(s): Otsuki Y, Yamasaki J, Suina K, Okazaki S, Koike N, Saya H, Nagano O.
  • Journal Title: Cancer Science Volume: 111 Issue: 1 Pages: 127-136
  • DOI: 10.1111/cas.14224
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel functional anti-HER3 monoclonal antibodies with potent anti- cancer effects on various human epithelial cancers. (2020)
  • Author(s): Okita K, Okazaki S, Uejima S, Yamada E, Kaminaka H, Kondo M, Ueda S, Tokiwa R, Iwata R, Yamasaki A, Hayashi N, Ogura D, Hirotani K, Yoshioka T, Inoue M, Masuko K, Masuko T
  • Journal Title: Oncotarget Volume: 11 Issue: 1 Pages: 31-45
  • DOI: 10.18632/oncotarget.27414
  • NAID: 120006888520
  • Peer Reviewed / Open Access
• [Journal Article] Endothelial-Mesenchymal Transition Drives Expression of CD44 Variant and xCT in Pulmonary Hypertension (2019)
  • Author(s): Isobe Sarasa、Kataoka Masaharu、Endo Jin、Moriyama Hidenori、Okazaki Shogo、Tsuchihashi Kenji、Katsumata Yoshinori、Yamamoto Tsunehisa、Shirakawa Kohsuke、Yoshida Naohiro、Shimoda Masayuki、Chiba Tomohiro、Masuko Takashi、Hakamata Yoji、Kobayashi Eiji、Saya Hideyuki、Fukuda Keiichi、Sano Motoaki
  • Journal Title: American Journal of Respiratory Cell and Molecular Biology Volume: Volume61,Issue3 Issue: 3 Pages: 367-379
  • DOI: 10.1165/rcmb.2018-0231oc
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Glutaminolysis-related genes determine sensitivity to xCT-targeted therapy in head and neck squamous cell carcinoma. (2019)
  • Author(s): Okazaki S, Umene K, Yamasaki J, Suina K, Otsuki Y, Yoshikawa M, Minami Y, Masuko T, Kawaguchi S, Nakayama H, Banno K, Aoki D, Saya H, Nagano O.
  • Journal Title: Cancer Science Volume: 110 Issue: 11 Pages: 3453-3463
  • DOI: 10.1111/cas.14182
  • Peer Reviewed / Open Access
• [Journal Article] Transcription factor Tlx1 marks a subset of lymphoid tissue organizer-like mesenchymal progenitor cells in the neonatal spleen (2019)
  • Author(s): Ueno Yuta、Fujisaki Keiko、Hosoda Shoko、Amemiya Yusuke、Okazaki Shogo、Notsu Chihiro、Nishiyama Chiharu、Mabuchi Yo、Matsuzaki Yumi、Oda Akihisa、Goitsuka Ryo
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 20408-20408
  • DOI: 10.1038/s41598-019-56984-w
  • Peer Reviewed / Open Access
• [Journal Article] Sulfasalazine could modulate the CD 44v9‐xCT system and enhance cisplatin‐induced cytotoxic effects in metastatic bladder cancer (2019)
  • Author(s): Ogihara Koichiro、Kikuchi Eiji、Okazaki Shogo、Hagiwara Masayuki、Takeda Toshikazu、Matsumoto Kazuhiro、Kosaka Takeo、Mikami Shuji、Saya Hideyuki、Oya Mototsugu
  • Journal Title: Cancer Science Volume: 110 Issue: 4 Pages: 1431-1441
  • DOI: 10.1111/cas.13960
  • Peer Reviewed / Open Access
• [Journal Article] Anti‐tumor effects of mAb against l‐type amino acid transporter 1 (LAT1) bound to human and monkey LAT1 with dual avidity modes (2019)
  • Author(s): Ueda Shiho、Hayashi Hidemi、Miyamoto Takako、Abe Shinya、Hirai Kana、Matsukura Kanji、Yagi Hideki、Hara Yuta、Yoshida Kinji、Okazaki Shogo、Tamura Masakazu、Abe Yuki、Agatsuma Toshinori、Niwa Shin‐ichiro、Masuko Kazue、Masuko Takashi
  • Journal Title: Cancer Science Volume: 110 Issue: 2 Pages: 674-685
  • DOI: 10.1111/cas.13908
  • Peer Reviewed / Open Access
• [Journal Article] Synthetic lethality of the ALDH3A1 inhibitor dyclonine and xCT inhibitors in glutathione deficiency-resistant cancer cells (2018)
  • Author(s): Okazaki Shogo、Shintani Subaru、Hirata Yuki、Suina Kentaro、Semba Takashi、Yamasaki Juntaro、Umene Kiyoko、Ishikawa Miyuki、Saya Hideyuki、Nagano Osamu
  • Journal Title: Oncotarget Volume: 9 Issue: 73 Pages: 33832-33843
  • DOI: 10.18632/oncotarget.26112
  • Peer Reviewed / Open Access
• [Journal Article] EGFR promotes glioma progression by regulating xCT and GluN2B-containing NMDA receptor signaling. (2018)
  • Author(s): Suina K, Tsuchihashi K, Yamasaki J, Kamenori S, Shintani S, Hirata Y, Okazaki S, Sampetrean O, Baba E, Akashi K, Takahashi F, Takahashi K, Saya H, Nagano O.
  • Journal Title: Cancer Science Volume: 109 Issue: 12 Pages: 3874-3882
  • DOI: 10.1111/cas.13826
  • Peer Reviewed / Open Access
• [Presentation] Accumulation of leukemic cells to the spleen is regulated by a transcription factor Tlx1 expressed in perifollicular mesenchymal cells. (2019)
  • Author(s): Yusuke Amemiya, Shogo Okazaki, Chiharu Nishiyama, Takuro Nakamura and Ryo Goitsuka
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] Genetic labeling of neonatal CXCR5-expressing cells for tracking long-lived B-1 cells in the adults. (2019)
  • Author(s): Keiko Fujisaki, Shogo Okazaki and Chiharu Nishiyama, Yohsuke Harada, and Ryo Goitsuka
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] Recruitment of peritoneal B-1a cells to the spleen is regulated by the perifollicular mesenchymal niche. (2019)
  • Author(s): Shoko Hosoda, Shogo Okazaki and Chiharu Nishiyama and Ryo Goitsuka
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] FOXA1 expression confers resistance to xCT-targeted therapy in HNSCC (2019)
  • Author(s): Shogo Okazaki, Subaru Shintani, Hideyuki Saya and Osamu Nagano
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Extramedullary leukemogenic niche in the spleen exacerbates the progression of acute myeloid leukemia. (2019)
  • Author(s): Yusuke Amemiya, Shogo Okazaki, Takuro Nakamura and Ryo Goitsuka
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] xCT confers cancer stem like properties in small cell lung cancer cells. (2019)
  • Author(s): Kentaro Suina, Juntaro Yamasaki, Yuji Otsuki, Yuki Hirata, Shogo Okazaki, Kenji Tsuchihashi, Oltea Sampetrean, Yoichiro Mitsuishi, Fumiyuki Takahashi, Kazuhisa Takahashi, Hideyuki Saya, Osamu Nagano
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Benzaldehyde activates AMPK via cancer specific upregulated 14-3-3ζ (2019)
  • Author(s): 7.Jun Saitoh, Nobuyuki Onishi, Eiji Sugihara, Takatsune Simizu, Kiyomi Kimura, Naoyoshi Koike, Oltea Sampetrean, Shogo Okazaki, Hiroyuki Nobusue, Takashi Kasama, Hideyuki Saya
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] 脾臓微小環境による骨髄自然制御性プラズマブラストの分化・移行制御 (2019)
  • Author(s): 藤崎桂子、西山千春、岡崎章悟、後飯塚僚
  • Organizer: 第29回Kyoto T cell conference (KTCC)
• [Presentation] 転写因子Tlx1を発現する成体脾臓微小環境による腹腔B-1a細胞の脾臓への移行制御 (2019)
  • Author(s): 細田祥子、藤崎桂子、西山千春、原田陽介、岡崎章悟、後飯塚僚
  • Organizer: 第29回学術集会Kyoto T cell conference (KTCC)
• [Presentation] BRD4 regulates the expression of Livin and thereby confers resistance to Fas-mediated immune cytotoxicity in aggressive B-cell lymphoma. (2019)
  • Author(s): Sugihara Eiji, Norisato Hashimoto, Satoru Osuka, Sayaka Ueno, Takatsune Shimizu, Shogo Okazaki, Taka-aki Sato, Shinichiro Okamoto, Hideyuki Saya
  • Organizer: AACR Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] SLC7A11 expression confers cancer stem-like properties in small cell lung cancer cells. (2019)
  • Author(s): Shohei Kamenori, Kentaro Suina, Juntaro Yamasaki, Subaru Shintani, Yuji Otsuki, Yuki Hirata, Shogo Okazaki, Kenji Tsuchihashi,Oltea Sampetrean, Yoichiro Mitsuishi, Fumiyuki Takahashi, Kazuhisa Takahashi, Hideyuki Saya, Osamu Nagano
  • Organizer: AACR Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] Combinatorial inhibition of xCT and ALDH3A1 induces synthetic lethality in xCT inhibitor-resistant cancer cells (2018)
  • Author(s): Shogo Okazaki, Subaru Shintani, Yuki Hirata, Hideyuki Saya, Osamu Nagano
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Benzaldehyde inhibits the multiple signals and E2F transcription in cancer cells by suppression of overexpressed 14-3-3ζ (2018)
  • Author(s): Jun Saitoh, Nobuyuki Onishi, Eiji Sugihara, Shogo Okazaki, Hiroyuki Nobusue, Takashi Kasama, Hideyuki Saya
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] A novel gastric cancer mouse model by using organoid technique and genetic manipulation (2018)
  • Author(s): Yuki Hirata, Osamu Nagano, Yoshiyuki Saito, Juntaro Yamasaki, Subaru Shintani, Kentaro Suina, Shogo Okazaki, Hirofumi Kawakubo, Hideyuki Saya, Yuko Kitagawa
  • Organizer: 第77回日本癌学会学術総会