Analysis of cellular response to acidification of tumor microenvironments

• Project/Area Number: 20H03515
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kyoto University (2022); Osaka University (2020-2021)
• Principal Investigator: Miki Hiroaki 京都大学, 工学研究科, 教授 (80302602)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2022: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2021: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2020: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: がん / リソソーム / 酸性環境

Outline of Research at the Start

体内のpHは通常7.4前後に維持されているが、がん細胞が増殖してがん組織が大きく広がると共にその周辺組織は酸性化してゆく。酸性環境は細胞増殖を妨げるなど、通常の細胞にとって害を及ぼすものだが、悪性化したがん細胞はその中でも増殖を続けてゆく。私たちはこのがん細胞の特性とも言える酸性環境適応に関わる遺伝子を見つけており、この研究ではその具体的な機能メカニズムを明らかにしてゆく。

Outline of Final Research Achievements

In this study, we investigated the cellular adaptation to acidic environments, which is caused by overexpression of PRL, a molecule driving cancer malignancy. We found that lysosomal exocytosis occurs actively in PRL-overexpressing cells, releasing protons to the cell exterior and thereby maintaining intracellular pH even under acidic conditions. We also discovered that specific signaling activates lysosomal exocytosis.

Academic Significance and Societal Importance of the Research Achievements

悪性化したがん組織が酸性化していることは古くから知られてきたが、がん細胞の応答機構は長らく不明だった。本研究では、がん細胞がリソソームの膜動態を調節することで積極的にプロトンを排出して、酸性環境に適応してゆく仕組みを新たに発見することができた。がん悪性化の本態をその周辺環境との関わりの中で理解し、また、がんの人為的コントロールに道を開く重要な研究成果と評価できる。

Research Products

• [Int'l Joint Research] Fudan University(中国)
• [Journal Article] PRL stimulates mitotic errors by suppressing kinetochore-localized activation of AMPK during mitosis (2022)
  • Author(s): Ryu Kajung、Yoshida Atsushi、Funato Yosuke、Yamazaki Daisuke、Miki Hiroaki
  • Journal Title: Cell Structure and Function Volume: 47 Issue: 2 Pages: 75-87
  • DOI: 10.1247/csf.22034
  • ISSN: 0386-7196, 1347-3700
  • Peer Reviewed / Open Access
• [Journal Article] Phosphatase‐independent role of phosphatase of regenerating liver in cancer progression (2022)
  • Author(s): Funato Yosuke、Hashizume Osamu、Miki Hiroaki
  • Journal Title: Cancer Science Volume: 114 Issue: 1 Pages: 25-33
  • DOI: 10.1111/cas.15625
  • Peer Reviewed / Open Access
• [Journal Article] A novel role for PRL in regulating epithelial cell density by inducing apoptosis at confluence (2022)
  • Author(s): Lohani Sweksha、Funato Yosuke、Akieda Yuki、Mizutani Kiyohito、Takai Yoshimi、Ishitani Tohru、Miki Hiroaki
  • Journal Title: Journal of Cell Science Volume: 135 Issue: 2 Pages: 1-14
  • DOI: 10.1242/jcs.258550
  • Peer Reviewed / Open Access
• [Journal Article] The emerging roles and therapeutic potential of cyclin M/CorC family of Mg2+ transporters (2022)
  • Author(s): Funato Yosuke、Miki Hiroaki
  • Journal Title: Journal of Pharmacological Sciences Volume: 148 Issue: 1 Pages: 14-18
  • DOI: 10.1016/j.jphs.2021.09.004
  • Peer Reviewed / Open Access
• [Journal Article] Gut bacteria identified in colorectal cancer patients promote tumourigenesis via butyrate secretion (2021)
  • Author(s): Okumura Shintaro、Konishi Yusuke、Narukawa Megumi、Sugiura Yuki、Yoshimoto Shin、Arai Yuriko、Sato Shintaro、Yoshida Yasuo、Tsuji Shunya、Uemura Ken、Wakita Masahiro、Matsudaira Tatsuyuki、Matsumoto Tomonori、Kawamoto Shimpei、Takahashi Akiko、Itatani Yoshiro、Miki Hiroaki ら
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 5674-5674
  • DOI: 10.1038/s41467-021-25965-x
  • Peer Reviewed / Open Access
• [Journal Article] Importance of the renal ion channel TRPM6 in the circadian secretion of renin to raise blood pressure (2021)
  • Author(s): Funato Yosuke、Yamazaki Daisuke、Okuzaki Daisuke、Yamamoto Nobuhiko、Miki Hiroaki
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 3683-3683
  • DOI: 10.1038/s41467-021-24063-2
  • Peer Reviewed / Open Access
• [Journal Article] Identification and mechanistic analysis of an inhibitor of the CorC Mg2+ transporter (2021)
  • Author(s): Huang Yichen、Mu Kaijie、Teng Xinyu、Zhao Yimeng、Funato Yosuke、Miki Hiroaki、Zhu Weiliang、Xu Zhijian、Hattori Motoyuki
  • Journal Title: iScience Volume: 24 Issue: 4 Pages: 102370-102370
  • DOI: 10.1016/j.isci.2021.102370
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of adenomatous polyposis coli in proliferation and differentiation of colon epithelial cells in organoid culture (2021)
  • Author(s): Yamazaki Daisuke、Hashizume Osamu、Taniguchi Shiho、Funato Yosuke、Miki Hiroaki
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 3980-3980
  • DOI: 10.1038/s41598-021-83590-6
  • Peer Reviewed / Open Access
• [Journal Article] Structural basis for the Mg2+ recognition and regulation of the CorC Mg2+ transporter (2021)
  • Author(s): Huang Yichen、Jin Fei、Funato Yosuke、Xu Zhijian、Zhu Weiliang、Wang Jing、Sun Minxuan、Zhao Yimeng、Yu Ye、Miki Hiroaki、Hattori Motoyuki
  • Journal Title: Science Advances Volume: 7 Issue: 7
  • DOI: 10.1126/sciadv.abe6140
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Phosphatase, pseudo-phosphatase, or both? Understanding PRL oncogenicity (2020)
  • Author(s): Gehring Kalle、Miki Hiroaki
  • Journal Title: British Journal of Cancer Volume: 124 Issue: 6 Pages: 1035-1036
  • DOI: 10.1038/s41416-020-01194-9
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The Oncogenic PRL Protein Causes Acid Addiction of Cells by Stimulating Lysosomal Exocytosis. (2020)
  • Author(s): Yosuke Funato, Atsushi Yoshida, Yusuke Hirata, Osamu Hashizume, Daisuke Yamazaki, Hiroaki Miki
  • Journal Title: Developmental cell Volume: 55 Issue: 4 Pages: 387-397
  • DOI: 10.1016/j.devcel.2020.08.009
  • Peer Reviewed / Open Access
• [Journal Article] Magnesium efflux from Drosophila Kenyon cells is critical for normal and diet-enhanced long-term memory (2020)
  • Author(s): Wu Yanying、Funato Yosuke、Meschi Eleonora、Jovanoski Kristijan D、Miki Hiroaki、Waddell Scott
  • Journal Title: eLife Volume: 9
  • DOI: 10.7554/elife.61339
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PRL3 pseudophosphatase activity is necessary and sufficient to promote metastatic growth (2020)
  • Author(s): Kozlov Guennadi、Funato Yosuke、Chen Yu Seby、Zhang Zhidian、Illes Katalin、Miki Hiroaki、Gehring Kalle
  • Journal Title: Journal of Biological Chemistry Volume: 295 Issue: 33 Pages: 11682-11692
  • DOI: 10.1074/jbc.ra120.014464
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Excessive Mg 2+ Impairs Intestinal Homeostasis by Enhanced Production of Adenosine Triphosphate and Reactive Oxygen Species (2020)
  • Author(s): Osamu Hashizume , Yosuke Funato , Daisuke Yamazaki, Hiroaki Miki
  • Journal Title: Antioxid Redox Signal . Volume: - Issue: 1 Pages: 20-34
  • DOI: 10.1089/ars.2019.7951
  • Peer Reviewed
• [Journal Article] p18/Lamtor1-mTORC1 Signaling Controls Development of Mucin-producing Goblet Cells in the Intestine (2020)
  • Author(s): Ito Shizuka、Nada Shigeyuki、Yamazaki Daisuke、Kimura Tetsuya、Kajiwara Kentaro、Miki Hiroaki、Okada Masato
  • Journal Title: Cell Structure and Function Volume: 45 Issue: 2 Pages: 93-105
  • DOI: 10.1247/csf.20018
  • NAID: 130007871371
  • ISSN: 0386-7196, 1347-3700
  • Peer Reviewed / Open Access
• [Journal Article] Stress-responsive MTK1 SAPKKK serves as a redox sensor that mediates delayed and sustained activation of SAPKs by oxidative stress (2020)
  • Author(s): Matsushita Moe、Nakamura Takanori、Moriizumi Hisashi、Miki Hiroaki、Takekawa Mutsuhiro
  • Journal Title: Science Advances Volume: 6 Issue: 26 Pages: 1-1
  • DOI: 10.1126/sciadv.aay9778
  • Peer Reviewed / Open Access
• [Presentation] マグネシウム調節の分子病態生化学 (2023)
  • Author(s): 三木 裕明
  • Organizer: SBCセミナー
  • Invited
• [Presentation] 活性硫黄の化学修飾による発がん因子PRLの機能制御 (2022)
  • Author(s): 三木 裕明、船戸 洋佑
  • Organizer: 第９５回日本生化学会大会
  • Invited
• [Presentation] Regulation of oncogenic protein PRL by diverse chemical modifications of its active cysteine (2022)
  • Author(s): Hiroaki Miki, Yosuke Funato
  • Organizer: Redox Week in Sendai 2022
  • Int'l Joint Research / Invited
• [Presentation] Mg2+トランスポーターCNNMの生物学的重要性と治療標的としての可能性 (2022)
  • Author(s): 船戸洋佑、橋爪脩、山崎大輔、三木裕明
  • Organizer: 第95回日本薬理学会年会
  • Invited
• [Presentation] Maintenance of magnesium homeostasis by CNNM and various diseases caused by its disruption (2022)
  • Author(s): Yosuke Funato, Osamu Hashizume, Daisuke Yamazaki, Hiroaki Miki
  • Organizer: 第99回日本生理学会大会
  • Invited
• [Presentation] 発がん因子PRLの活性中心システイン硫黄原子の化学修飾による機能制御 (2022)
  • Author(s): 三木 裕明、船戸 洋佑
  • Organizer: レドックスR&D戦略委員会 春のシンポジウム
  • Invited
• [Presentation] A novel role of PRL in regulating epithelial cell density by inducing apoptosis at confluence (2021)
  • Author(s): Sweksha Lohani, 船戸 洋佑, 龝枝 佑紀, 石谷 太, 三木 裕明
  • Organizer: 生理研研究会『上皮膜輸送の多様性・調和機構を基盤とする異分野融合研究の創出』
• [Presentation] がん細胞の酸性環境適応機構「acid addiction」の分子メカニズム解析 (2021)
  • Author(s): 船戸洋佑、本田茉子、山崎大輔、三木裕明
  • Organizer: 第94回日本生化学会大会
  • Invited
• [Presentation] 大腸がん浸潤・転移に関与するがん細胞の探索 (2021)
  • Author(s): 山崎 大輔、三木 裕明
  • Organizer: 第44回日本分子生物学会年会
• [Presentation] cnnm変異により線虫のボディサイズが縮小する仕組みの解析 (2021)
  • Author(s): 橋爪 脩、川邊 智史、船戸 洋佑、三木 裕明
  • Organizer: 第44回日本分子生物学会年会
• [Presentation] CNNMによるマグネシウムの輸送とその医学生物学的重要性 (2020)
  • Author(s): 船戸 洋佑, 橋爪 脩, 吉田 篤, 山崎 大輔, 三木 裕明
  • Organizer: 生理研研究会『上皮膜輸送の多様性・調和機構を基盤とする異分野融合研究の創出』
  • Invited
• [Presentation] がん細胞の酸性環境への新規適応機構「acid addiction」の発見 (2020)
  • Author(s): 船戸 洋佑, 橋爪 脩, 吉田 篤, 本田 茉子, 山崎 大輔, 三木 裕明
  • Organizer: 第93回日本生化学会大会
  • Invited
• [Presentation] 活性システインのリン酸化による細胞機能制御 (2020)
  • Author(s): 三木 裕明, 船戸 洋佑, 山崎 大輔
  • Organizer: 第93回日本生化学会大会
  • Invited
• [Presentation] アポトーシスを誘導することで上皮細胞密度を決定する (2020)
  • Author(s): ロハニ スウェクサ, 船戸 洋佑, 三木 裕明
  • Organizer: 第43回日本分子生物学会年会
• [Presentation] 標的既知化合物スクリーニングによる酸性環境適応におけるTGF-β経路の重要性の解明 (2020)
  • Author(s): 本田 茉子, 船戸 洋佑, 三木 裕明
  • Organizer: 第43回日本分子生物学会年会
• [Presentation] オルガノイド培養を用いた大腸上皮細胞の増殖および分化におけるAPCの役割の解析 (2020)
  • Author(s): 山崎 大輔, 橋爪 修, 谷口 詩歩, 船戸 洋祐, 三木 裕明
  • Organizer: 第43回日本分子生物学会年会
• [Presentation] がんの悪性化と酸性環境適応の分子機構 (2020)
  • Author(s): 三木 裕明
  • Organizer: 第71回日本電気泳動学会総会
  • Invited