Analyses of physiological function of PGRMC1 based on the structural regulation

• Project/Area Number: 18K06921
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: Keio University
• Principal Investigator: Kabe Yasuaki 慶應義塾大学, 医学部(信濃町), 准教授 (20397037)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: ヘム / 癌 / 脂質代謝 / 金属タンパク質 / 天然有機化合物 / 結晶構造解析 / アポトーシス

Outline of Final Research Achievements

Based on our analyses on the structural regulation of the membrane protein PGRMC1, we have performed chemical screening targeting PGRMC1. We found that these candidate compounds suppress PGRMC1-mediated cancer development in the cancer cells and mouse tumor transplantation model, via inhibition of the binding between PGRMC1 and EGFR. Furthermore, analyses using PGRMC1 cKO mice revealed that PGRMC1 promotes adipocyte lipid accumulation and exhibits an obesity-enhancing function in an obesity model on a high-fat diet (Commun Biol, 2020). Since the cadicate drugs suppress the PGRMC1-mediated lipid accumulation, optimization of candidate drugs will lead to the development of new therapeutic treatment for cancer and metabolic syndrome.

Academic Significance and Societal Importance of the Research Achievements

本研究は、ヘムの細胞内標的分子の網羅的同定というケミカルバイオロジー的な解析を出発点として、分子生物学、構造生物学、細胞生物学、生理学など様々な研究手法を融合させた極めて学際性の高い独創的な研究であるといえる。これらの解析により、未知であったPGRMC1の癌や肝炎などの炎症に対する作用の解明が期待できる。さらにPGRMC1に結合する薬剤も見出しており、この結合様式や制御機構を解明することにより、PGRMC1が関わる疾患に対する予防法や創薬開発の基盤となると考えられ、社会的な意義も非常に大きく成果の発展が期待される。

Research Products

• [Journal Article] On-tissue polysulfide visualization by surface-enhanced Raman spectroscopy benefits patients with ovarian cancer to predict post-operative chemosensitivity (2021)
  • Author(s): Honda Kazufumi、Hishiki Takako、Yamamoto Sohe、Naito Yoshiko、Matsuura Tomomi、Iwaisako Keiko、Masui Toshihiko、Sakuma Tomohiro、Matsubara Osamu、Huang Wilber、Ida Tomoaki、Akaike Takaaki、Masugi Yohei、Sakamoto Michiie、Kato Tomoyasu、Kabe Yasuaki、Suematsu Makoto
  • Journal Title: Redox Biology Volume: 41 Pages: 101926-101926
  • DOI: 10.1016/j.redox.2021.101926
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Short-chain fatty acids bind to apoptosis-associated speck-like protein to activate inflammasome complex to prevent Salmonella infection (2020)
  • Author(s): Tsugawa Hitoshi、Kabe Yasuaki、Kanai Ayaka、Sugiura Yuki、Hida Shigeaki、Taniguchi Shun’ichiro、Takahashi Toshio、Matsui Hidenori、Yasukawa Zenta、Itou Hiroyuki、Takubo Keiyo、Suzuki Hidekazu、Honda Kenya、Handa Hiroshi、Suematsu Makoto
  • Journal Title: PLOS Biology Volume: 18 Issue: 9 Pages: 3000813-3000813
  • DOI: 10.1371/journal.pbio.3000813
  • Peer Reviewed / Open Access
• [Journal Article] Progesterone receptor membrane associated component 1 enhances obesity progression in mice by facilitating lipid accumulation in adipocytes (2020)
  • Author(s): Furuhata Ryogo、Kabe Yasuaki、Kanai Ayaka、Sugiura Yuki、Tsugawa Hitoshi、Sugiyama Eiji、Hirai Miwa、Yamamoto Takehiro、Koike Ikko、Yoshikawa Noritada、Tanaka Hirotoshi、Koseki Masahiro、Nakae Jun、Matsumoto Morio、Nakamura Masaya、Suematsu Makoto
  • Journal Title: Communications Biology Volume: 3 Issue: 1 Pages: 479-479
  • DOI: 10.1038/s42003-020-01202-x
  • Peer Reviewed / Open Access
• [Journal Article] O-Glycan-Altered Extracellular Vesicles: A Specific Serum Marker Elevated in Pancreatic Cancer (2020)
  • Author(s): Yokose, T., et al., Koshiba, S., et al., Kitagawa, Y.（合計32名、本研究者は26番目）
  • Journal Title: Cancers Volume: 12 Issue: 9 Pages: 2469-2469
  • DOI: 10.3390/cancers12092469
  • Peer Reviewed / Open Access
• [Journal Article] Comparative Glycomic Analysis of Exosome Subpopulations Derived from Pancreatic Cancer Cell Lines (2020)
  • Author(s): Matsuda Atsushi、Kuno Atsushi、Yoshida Maki、Wagatsuma Takanori、Sato Takashi、Miyagishi Makoto、Zhao Jing、Suematsu Makoto、Kabe Yasuaki、Narimatsu Hisashi
  • Journal Title: Journal of Proteome Research Volume: 19 Issue: 6 Pages: 2516-2524
  • DOI: 10.1021/acs.jproteome.0c00200
  • Peer Reviewed / Open Access
• [Journal Article] Annexin A1 accounts for an anti-inflammatory binding target of sesamin metabolites. (2020)
  • Author(s): Kabe Y, Takemoto D, Kanai A, Hirai M, Ono Y, Akazawa S, Horikawa M, Kitagawa Y, Handa H, Rogi T, Shibata H, Suematsu M.
  • Journal Title: npj Science of Food Volume: 4 Issue: 1
  • DOI: 10.1038/s41538-020-0064-6
  • Peer Reviewed / Open Access
• [Journal Article] Xanthine oxidase inhibitor ameliorates postischemic renal injury in mice by promoting resynthesis of adenine nucleotides. (2019)
  • Author(s): Fujii K, Kubo A, Miyashita K, Sato M, Hagiwara A, Inoue H, Ryuzaki M, Tamaki M, Hishiki T, Hayakawa N, Kabe Y, Itoh H, Suematsu M.
  • Journal Title: JCI insight Volume: 4 Issue: 22 Pages: 124816-124816
  • DOI: 10.1172/jci.insight.124816
  • Peer Reviewed / Open Access
• [Journal Article] Environmental Optimization Enables Maintenance of Quiescent Hematopoietic Stem Cells Ex Vivo. (2019)
  • Author(s): Kobayashi H, Morikawa T, Okinaga A, Hamano F, Hashidate-Yoshida T, Watanuki S, Hishikawa D, Shindou H, Arai F, Kabe Y, Suematsu M, Shimizu T, Takubo K.
  • Journal Title: Cell Reports Volume: 28 Issue: 1 Pages: 145-158
  • DOI: 10.1016/j.celrep.2019.06.008
  • Peer Reviewed / Open Access
• [Journal Article] Application of high-performance magnetic nanobeads to biological sensing devices (2019)
  • Author(s): Kabe Yasuaki、Sakamoto Satoshi、Hatakeyama Mamoru、Yamaguchi Yuki、Suematsu Makoto、Itonaga Makoto、Handa Hiroshi
  • Journal Title: Analytical and Bioanalytical Chemistry Volume: 411 Issue: 9 Pages: 1825-1837
  • DOI: 10.1007/s00216-018-1548-y
  • Peer Reviewed / Open Access
• [Journal Article] Function and structural regulation of the carbon monoxide (CO)-responsive membrane protein PGRMC1 (2018)
  • Author(s): Kabe Y, Handa H, Suematsu M.
  • Journal Title: Journal of Clinical Biochemistry and Nutrition Volume: 63 Issue: 1 Pages: 12-17
  • DOI: 10.3164/jcbn.17-132
  • NAID: 130007387128
  • ISSN: 0912-0009, 1880-5086
  • Peer Reviewed / Open Access
• [Journal Article] Development of a Highly Sensitive Device for Counting the Number of Disease-Specific Exosomes in Human Sera. (2018)
  • Author(s): Kabe Y, Suematsu M, Sakamoto S, Hirai M, Koike I, Hishiki T, Matsuda A, Hasegawa Y, Tsujita K, Ono M, Minegishi N, Hozawa A, Murakami Y, Kubo M, Itonaga M, Handa H.
  • Journal Title: Clin Chem Volume: 64 Issue: 10 Pages: 1463-1473
  • DOI: 10.1373/clinchem.2018.291963
  • Peer Reviewed / Open Access
• [Journal Article] Baicalein Targets GTPase-Mediated Autophagy to Eliminate Liver Tumor-Initiating Stem Cell-Like Cells Resistant to mTORC1 Inhibition. (2018)
  • Author(s): Wu R, Murali R, Kabe Y, French SW, Chiang YM, Liu S, Sher L, Wang CC, Louie S, Tsukamoto H.
  • Journal Title: Hepatology Volume: 68 Issue: 5 Pages: 1726-1740
  • DOI: 10.1002/hep.30071
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gold-nanofève surface-enhanced Raman spectroscopy visualizes hypotaurine as a robust anti-oxidant consumed in cancer survival (2018)
  • Author(s): Shiota M, Naya M, Yamamoto T, Hishiki T, Tani T, Takahashi H, Kubo A, Koike D, Itoh M, Ohmura M, Kabe Y, Sugiura Y, Hiraoka N, Morikawa T, Takubo K, Suina K, Nagashima H, Sampetrean O, Nagano O, Saya H, Yamazoe S, Watanabe H, Suematsu M
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 1561-1561
  • DOI: 10.1038/s41467-018-03899-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Development of a medical application using nano-beads technology (2019)
  • Author(s): Yasuaki Kabe
  • Organizer: The 92nd Annual Meeting of the Japanese Biochemical Society
  • Int'l Joint Research / Invited
• [Patent(Industrial Property Rights)] 膵臓がん検出方法及び膵臓がん検出キット (2020)
  • Inventor(s): 株式会社JVCケンウッド、学校法人慶應義塾
  • Industrial Property Rights Holder: 株式会社JVCケンウッド、学校法人慶應義塾
  • Industrial Property Rights Type: 特許
  • Filing Date: 2020