Antitumor drug development research focusing on the novel cancer cell regulation mechanism of PRIP

• Project/Area Number: 17K11644
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Functional basic dentistry
• Research Institution: Hiroshima University
• Principal Investigator: Asano Satoshi 広島大学, 医系科学研究科(歯), 助教 (30570535)
• Co-Investigator(Kenkyū-buntansha): 兼松 隆 九州大学, 歯学研究院, 教授 (10264053)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 細胞分裂 / 細胞質分裂 / RhoA / OCRL1 / PI(4,5)P2 / ミオシンII / シスプラチン / アポトーシス / 乳癌 / PI3K / AKT / 細胞周期 / 乳がん / 癌 / 細胞移動 / 細胞増殖

Outline of Final Research Achievements

Cytokinesis is the last step of cell division that physically separates the daughter cells. Cytokinesis failure contributes to the development of pathologies such as cancer. Phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] accumulates at the cleavage furrow and is involved in Rho-type GTPase RhoA-dependent furrow ingression during cytokinesis. Here, we showed that PRIP is required for the localization of PI(4,5)P2 to the cleavage furrow. PRIP knockdown caused abnormal cytokinesis such as a furrow regression and cytokinesis delay. Fluorescence microscopy analysis confirmed weak localization of RhoA and phosphorylated myosin II regulatory light chain (MRLC), which upregulates myosin II motor activity for furrow ingression, in cleavage furrow in HeLa cells reduced PRIP. These results suggest that PRIP is required for stable maintenance of PI(4,5)P2 in the cleavage furrow, which is a prerequisite for the RhoA signaling-dependent progression of cytokinesis.

Academic Significance and Societal Importance of the Research Achievements

本研究は、我々が見出し、癌細胞の増殖や転移抑制効果を確認したPRIPの分子機能に着目して、抗腫瘍薬開発を目指す基礎研究である。今回新たにPRIPが細胞質分裂にも関わっていることを明らかにした。正常細胞の細胞質分裂異常によって多核化が起こると、染色体が多倍体化するが、これは癌化の一因であると考えられている。本研究によってPRIPが細胞質分裂の正常化に寄与することと、そのメカニズムが明らかになったことで、癌化や癌の増悪化を抑制するPRIPをターゲットとした抗腫瘍薬の開発に繋がる意義深い研究になったと考える。

Research Products

• [Journal Article] Phospholipase C-related catalytically inactive protein regulates cytokinesis by protecting phosphatidylinositol 4,5-bisphosphate from metabolism in the cleavage furrow (2019)
  • Author(s): Asano, S., Ikura, Y., Nishimoto, M., Yamawaki, Y., Hamao, K., Kamijo, K., Hirata, M. and Kanematsu, T.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 12729-12729
  • DOI: 10.1038/s41598-019-49156-3
  • Peer Reviewed / Open Access
• [Journal Article] Phospholipase C-related catalytically inactive protein: A novel signaling molecule for modulating fat metabolism and energy expenditure (2019)
  • Author(s): Kanematsu T, Oue K, Okumura T, Harada K, Yamawaki Y, Asano S, Mizokami A, Irifune M, Hirata M
  • Journal Title: J Oral Biosci Volume: 61(2) Issue: 2 Pages: 65-72
  • DOI: 10.1016/j.job.2019.04.002
  • Peer Reviewed / Open Access
• [Journal Article] Phospholipase C-related catalytically inactive protein regulates lipopolysaccharide-induced hypothalamic inflammation-mediated anorexia in mice (2019)
  • Author(s): Yamawaki Yosuke、Shirawachi Satomi、Mizokami Akiko、Nozaki Kanako、Ito Hikaru、Asano Satoshi、Oue Kana、Aizawa Hidenori、Yamawaki Shigeto、Hirata Masato、Kanematsu Takashi
  • Journal Title: Neurochemistry International Volume: 131 Pages: 104563-104563
  • DOI: 10.1016/j.neuint.2019.104563
  • Peer Reviewed / Open Access
• [Journal Article] Ccr7 null mice are protected against diet-induced obesity via Ucp1 upregulation and enhanced energy expenditure (2019)
  • Author(s): Sano Tomomi、Sanada Taiki、Sotomaru Yusuke、Shinjo Takanori、Iwashita Misaki、Yamashita Akiko、Fukuda Takao、Sanui Terukazu、Asano Tomoichiro、Kanematsu Takashi、Nishimura Fusanori
  • Journal Title: Nutrition & Metabolism Volume: 16 Issue: 1 Pages: 43-43
  • DOI: 10.1186/s12986-019-0372-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prolyl Isomerase Pin1 Suppresses Thermogenic Programs in Adipocytes by Promoting Degradation of Transcriptional Co-activator PRDM16. (2019)
  • Author(s): Nakatsu Y, Matsunaga Y, Yamamotoya T, Ueda K, Inoue MK, Mizuno Y, Nakanishi M, Sano T, Yamawaki Y, Kushiyama A, Sakoda H, Fujishiro M, Ryo A, Ono H, Minamino T, Takahashi SI, Ohno H, Yoneda M, Takahashi K, Ishihara H, Katagiri H, Nishimura F, Kanematsu T, Yamada T, Asano T.
  • Journal Title: Cell Rep. Volume: 26 Issue: 12 Pages: 3221-3230
  • DOI: 10.1016/j.celrep.2019.02.066
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phospholipase C-related inactive protein type-1 deficiency affects anesthetic electroencephalogram activity induced by propofol and etomidate in mice (2019)
  • Author(s): Furukawa T, Nikaido Y, Shimoyama S, Ogata Y, Kushikata T, Hirota K, Kanematsu T, Hirata M, Ueno S.
  • Journal Title: Journal of Anesthesia Volume: 33 Pages: 531-542
  • NAID: 40021971791
  • Peer Reviewed
• [Journal Article] Sodium butyrate abolishes lipopolysaccharide-induced depression-like behaviors and hippocampal microglial activation in mice (2018)
  • Author(s): Yamawaki Y, Yoshioka N, Nozaki K, Ito H, Oda K, Harada K, Shirawachi S, Asano S, Aizawa H, Yamawaki S, Kanematsu T, Akagi H
  • Journal Title: Brain research Volume: 1;1680 Pages: 13-38
  • DOI: 10.1016/j.brainres.2017.12.004
  • Peer Reviewed / Open Access
• [Journal Article] Suppression of cell migration by phospholipase C-related catalytically inactive protein-dependent modulation of PI3K signalling (2017)
  • Author(s): Asano Satoshi、Taniguchi Yuri、Yamawaki Yosuke、Gao Jing、Harada Kae、Takeuchi Hiroshi、Hirata Masato、Kanematsu Takashi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 5408-5408
  • DOI: 10.1038/s41598-017-05908-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] General anesthetic actions on GABAA receptors in vivo are reduced in phospholipase C-related catalytically inactive protein knockout mice. (2017)
  • Author(s): Hayashiuchi M, Kitayama T, Morita K, Yamawaki Y, Oue K, Yoshinaka T, Asano S, Harada K, Kang Y, Hirata M, Irifune M, Okada M, Kanematsu T.
  • Journal Title: Journal of Anesthesia Volume: in press Issue: 4 Pages: 531-538
  • DOI: 10.1007/s00540-017-2350-2
  • Peer Reviewed / Open Access
• [Journal Article] Phospholipase C-related catalytically inactive protein-knockout mice display increased induction of uncoupling protein 1 in adipose tissues following chronic cold exposure. (2017)
  • Author(s): Kana Oue, Yosuke Yamawaki, Satoshi Asano, Mizokami Akiko, Masato Hirata, Masahiro Irifune, Takashi Kanematsu.
  • Journal Title: Journal of Oral Biosciences Volume: 印刷中 Issue: 2 Pages: 108-112
  • DOI: 10.1016/j.job.2017.04.001
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Phospholipase C-related catalytically inactive protein can regulate obesity, a state of peripheral inflammation. (2017)
  • Author(s): Yamawaki Y, Oue K, Shirawachi S, Asano S, Harada K, Kanematsu T.
  • Journal Title: Japanese Dental Science Review Volume: 53（1） Issue: 1 Pages: 18-24
  • DOI: 10.1016/j.jdsr.2016.06.001
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] PRIP regulates talin1 dimerization by binding to its dimerization domain, and controls fibronectin/integrin-mediated cell adhesion (2019)
  • Author(s): Asano Satoshi, Kanematsu Takashi
  • Organizer: 第61回歯科基礎医学会学術大会
• [Presentation] 細胞接着に関与する新規タンパク質の発見と機能解析 (2019)
  • Author(s): 浅野智志、兼松隆
  • Organizer: 第14回 細胞運動研究会
• [Presentation] Regulation of cell adhesion by phospholipase C-related catalytically inactive protein (PRIP); PRIP directly promotes talin1 dimerization (2019)
  • Author(s): 浅野 智志、兼松 隆
  • Organizer: 第52回広島大学歯学会総会
• [Presentation] PRIP protects PI(4,5)P2 from its metabolic enzyme and contributes to completion of cytokinesis (2018)
  • Author(s): Yasuka Ikura, Asano Satoshi, Kanematsu Takashi
  • Organizer: 7th Hiroshima Conference
• [Presentation] Phospholipase C-related catalytically inactive protein regulates fat metabolism and energy expenditure (2018)
  • Author(s): Takashi Kanematsu, Kana Oue, Yosuke Yamawaki, Satoshi Asano
  • Organizer: 7th European Congress on Obesity and Eating Disorder, New Emerging Drifts and Tactic to Challenge Obesity and Eating Disorder
• [Presentation] PI(4,5)P2 metabolism regulator PRIP controls the metastatic potential in breast cancer cells (2018)
  • Author(s): Satoshi Asano, Takashi Kanematsu
  • Organizer: 第59回日本生化学会中国・四国支部例会
• [Presentation] PRIP modulates AKT-GSK3β signaling and regulates cell cycle progression (2018)
  • Author(s): Yuka Maetani, Satoshi Asano, Masahiro Irifune, Takashi Kanematsu
  • Organizer: 第51回広島大学歯学会
• [Presentation] Phospholipase C-related catalytically inactive protein regulates phosphatidylinositol metabolism and modulates cancer cell migration (2018)
  • Author(s): Takashi Kanematsu, Satoshi Asano, Yosuke Yamawaki, Satoru Kusaka
  • Organizer: 8th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] Phospholipase C-related catalytically inactive protein enhances cisplatin-induced apoptosis (2018)
  • Author(s): Satoshi Asano, Yuka Maetani, Yasuka Ikura, Takashi Kanematsu
  • Organizer: 8th World Congress of Basic and Clinical Pharmacology
  • Int'l Joint Research
• [Presentation] 新奇イノシトールリン脂質代謝調節タンパク質による乳がん細胞転移の制御機構の解明研究 (2018)
  • Author(s): 浅野智志
  • Organizer: 第60回歯科基礎医学会学術大会
  • Invited
• [Presentation] 白色・褐色脂肪細胞の機能を制御しエネルギー代謝を調節する新しい分子基盤 (2018)
  • Author(s): 兼松隆，大植香菜，坂田修三，山脇洋輔，浅野智志
  • Organizer: 第60回歯科基礎医学会学術大会
• [Presentation] PRIPの過剰発現で乳癌細胞の腫瘍増殖は抑制される (2018)
  • Author(s): 前谷有香，浅野智志，兼松隆
  • Organizer: 第60回歯科基礎医学会学術大会
• [Presentation] Phospholipase C-related catalytically inactive protein, a phosphatidylinositol metabolism regulator, controls the metastatic potential in breast cancer cells (2018)
  • Author(s): Takashi Kanematsu, Satoshi Asano
  • Organizer: The 8th Annual World Congress of Molecular & Cell Biology
• [Presentation] スフィンゴリピッド代謝酵素に着目した細胞質分裂を制御する新規タンパク質の探索研究 (2018)
  • Author(s): 浅野智志
  • Organizer: 歯科基礎医学会 平成30年度定時社員総会
• [Presentation] Expression of phospholipase C-related catalytically inactive protein suppresses cancerous metastasis (2017)
  • Author(s): Satoshi Asano, Takashi Kanematsu
  • Organizer: 第90回日本薬理学会年会
• [Presentation] Over expression of PRIP in MCF-7 cells, a breast cancer cell line, enhances cisplatin induced apoptosis (2017)
  • Author(s): Yuka Maetani, Satoshi Asano, Masahiro Irifune, Takashi Kanematsu
  • Organizer: 第50回広島大学歯学会
• [Presentation] Regulation of cytokinesis by phospholipase C-related catalytically inactive protein, as a sequestrant of PI(4,5)P2 in the cleavage furrow (2017)
  • Author(s): Satoshi Asano, Takashi Kanematsu
  • Organizer: 第59回歯科基礎医学会学術大会
• [Presentation] The mechanism of phospholipase C-related catalytically inactive protein (PRIP)-mediated energy metabolism by β-adrenergic stimulation in brown adipocytes (2017)
  • Author(s): 大植香菜，山脇洋輔，浅野智志，入舩正浩，兼松隆
  • Organizer: 第59回歯科基礎医学会学術大会