Analysis of the molecular basis of atypical cell-death induction with vacuolar formation in cancer cells by CDK4/6 inhibitors

• Project/Area Number: 18K15031
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: Nihon University (2019-2021); Tokyo Medical University (2018)
• Principal Investigator: HINO Hirotsugu 日本大学, 医学部, 助教 (30793468)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: abemaciclib / CDK4/6 / 自食胞形成 / 細胞死 / リソソーム / オートリソソーム / 分子スイッチ

Outline of Final Research Achievements

CDK4/6 inhibitor abemaciclib, which is used as anticancer drug, induces large vacuole formation in cytosol and causes cell death. In this study, we revealed that these large vacuoles induced by abemaciclib are swelling autolysosome. The vacuolar formation is independent of ATG5-related autophagy and is linked to cell death. It was also suggested that CDK4,6, main target of abemaciclib, functions as a target at least in part in the induction of vacuolar formation by abemaciclib. From these results, a part of mechanism in inducing large vacuolar formation in cytosol and in causing cell death is revealed.

Academic Significance and Societal Importance of the Research Achievements

本研究は抗がん剤として使用されているCDK4/6阻害薬による自食胞形成を伴った細胞死の誘導に着目し、CDK4/6による新規の細胞死様式を解明することを目指したものである。これらで得られる知見は、将来的にCDK4/6阻害薬と併用する薬剤の選択や適用の拡大、副作用の防止等の観点からも重要なものである。さらに、CDK4/6阻害薬abemaciclibによる自食胞形成は本来のCDK4/6のターゲットとは異なる標的分子にも作用した結果である可能性もあり、これまで想定されていたCDK4/6阻害薬の作用機序とは異なる、新たな作用機序の提唱に繋がると期待される。

Research Products

• [Journal Article] Age-related exacerbation of hematopoietic organ damage induced by systemic hyper-inflammation in senescence-accelerated mice (2021)
  • Author(s): Harada Tomonori、Tsuboi Isao、Hino Hirotsugu、Yuda Miyuki、Hirabayashi Yoko、Hirai Shuichi、Aizawa Shin
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 23250-23250
  • DOI: 10.1038/s41598-021-02621-4
  • Peer Reviewed / Open Access
• [Journal Article] Targeted disruption of GAK stagnates autophagic flux by disturbing lysosomal dynamics (2021)
  • Author(s): Miyazaki Masaya、Hiramoto Masaki、Takano Naoharu、Kokuba Hiroko、Takemura Jun、Tokuhisa Mayumi、Hino Hirotsugu、Kazama Hiromi、Miyazawa Keisuke
  • Journal Title: International Journal of Molecular Medicine Volume: 48 Issue: 4 Pages: 195-195
  • DOI: 10.3892/ijmm.2021.5028
  • Peer Reviewed / Open Access
• [Journal Article] Cytonuclear Estrogen Receptor Alpha Regulates Proliferation and Migration of Endometrial Carcinoma Cells (2021)
  • Author(s): Mierxiati Saimi, Shota Moriya, Zhong-Lian Li, Hidenobu Miyaso, Kenta Nagahori, Shinichi Kawata, Takuya Omotehara, Yuki Ogawa, Hirotsugu Hino, Keisuke Miyazawa, Kou Sakabe, Masahiro Itoh
  • Journal Title: The Tokai Journal of Experimental and Clinical Medicine Volume: 46 Pages: 7-16
  • Peer Reviewed
• [Journal Article] Kana Miyahara, Naoharu Takano, Yumiko Yamada, Hiromi Kazama, Mayumi Tokuhisa, Hirotsugu Hino, Koji Fujita, Edward Barroga, Masaki Hiramoto, Hiroshi Handa, Masahiko Kuroda, Takashi Ishikawa & Keisuke Miyazawa BRCA1 degradation in response to mitochondrial damage in breast cancer cells (2021)
  • Author(s): Kana Miyahara, Naoharu Takano, Yumiko Yamada, Hiromi Kazama, Mayumi Tokuhisa, Hirotsugu Hino, Koji Fujita, Edward Barroga, Masaki Hiramoto, Hiroshi Handa, Masahiko Kuroda, Takashi Ishikawa, Keisuke Miyazawa
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 8735-8735
  • DOI: 10.1038/s41598-021-87698-7
  • Peer Reviewed / Open Access
• [Journal Article] Sequestosome 1 (p62) accumulation in breast cancer cells suppresses progesterone receptor expression via argonaute 2 (2020)
  • Author(s): Yokota Ayuka、Hiramoto Masaki、Hino Hirotsugu、Tokuhisa Mayumi、Miyazaki Masaya、Kazama Hiromi、Takano Naoharu、Miyazawa Keisuke
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 531 Issue: 2 Pages: 256-263
  • DOI: 10.1016/j.bbrc.2020.07.058
  • Peer Reviewed / Open Access
• [Journal Article] Macrolide antibiotics enhance the antitumor effect of lansoprazole resulting in lysosomal membrane permeabilization?associated cell death (2020)
  • Author(s): Takeda Atsuo、Takano Naoharu、Kokuba Hiroko、Hino Hirotsugu、Moriya Shota、Abe Akihisa、Hiramoto Masaki、Tsukahara Kiyoaki、Miyazawa Keisuke
  • Journal Title: International Journal of Oncology Volume: 57 Issue: 6 Pages: 1280-1292
  • DOI: 10.3892/ijo.2020.5138
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of autophagy inducibility in various tyrosine kinase inhibitors and their enhanced cytotoxicity via inhibition of autophagy in cancer cells in combined treatment with azithromycin (2020)
  • Author(s): Tanaka Hideki、Hino Hirotsugu、Moriya Shota、Kazama Hiromi、Miyazaki Masaya、Takano Naoharu、Hiramoto Masaki、Tsukahara Kiyoaki、Miyazawa Keisuke
  • Journal Title: Biochemistry and Biophysics Reports Volume: 22 Pages: 100750-100750
  • DOI: 10.1016/j.bbrep.2020.100750
  • Peer Reviewed / Open Access
• [Journal Article] Abemaciclib induces atypical cell death in cancer cell characterized by formation of cytoplasmic vacuoles derived from lysosomes (2020)
  • Author(s): Hino Hirotsugu, Iriyama Noriyoshi, Kokuba Hiroko, Kazama Hiromi, Moriya Shota, Takano Naoharu, Hiramoto Masaki, Aizawa Shin, Miyazawa Keisuke
  • Journal Title: Cancer Science Volume: － Issue: 6 Pages: 2132-2145
  • DOI: 10.1111/cas.14419
  • Peer Reviewed / Open Access
• [Journal Article] Vitamin K2 induces non-apoptotic cell death along with autophagosome formation in breast cancer cell lines (2019)
  • Author(s): Miyazawa Shinsuke、Moriya Shota、Kokuba Hiroko、Hino Hirotsugu、Takano Naoharu、Miyazawa Keisuke
  • Journal Title: Breast Cancer Volume: 27 Issue: 2 Pages: 225-235
  • DOI: 10.1007/s12282-019-01012-y
  • Peer Reviewed
• [Journal Article] Fingolimod/FTY720 sensitizes EGFR wild-type non-small cell lung cancer cells to lapatinib or sorafenib and induces cell cycle arrest. (2019)
  • Author(s): Ohta K, Ohkuma T, Lorenzo AD, Yokota A, Hino H, Kazama H, Moriya S, Takano N, Hiramoto M, Miyazawa K.
  • Journal Title: Oncol Rep. Volume: - Pages: 231-242
  • DOI: 10.3892/or.2019.7140
  • Peer Reviewed / Int'l Joint Research
• [Presentation] CDK4/6阻害薬abemaciclibが誘導する空胞形成の機序及び細胞死との関連の検討 (2022)
  • Author(s): 日野浩嗣、田中良法、竹谷浩介、高野直治、平本正樹、相澤信、宮澤啓介、江藤真澄、平井宗一
  • Organizer: 第127回日本解剖学会総会・全国学術集会
• [Presentation] CDK4/6阻害薬abemaciclibが誘導する空胞の形成メカニズムの検討 (2021)
  • Author(s): 日野 浩嗣、田中 良法、竹谷 浩介、高野 直治、平本 正樹、相澤 信、宮澤 啓介、江藤 真澄、平井 宗一
  • Organizer: 第94回日本生化学会大会
• [Presentation] CDK4/6 inhibitor abemaciclib induces non-apoptotic cell-death with cytoplasmic vacuolar formation derived from lysosomes (2020)
  • Author(s): Hirotsugu Hino, Noriyoshi Iriyama, Hiroko Kokuba, Hiromi Kazama, Shota Moriya, Naoharu Takano, Masaki Hiramoto, Shin Aizawa, Keisuke Miyazawa
  • Organizer: 14th International Conference on Protein Phosphatase
  • Int'l Joint Research
• [Presentation] CDK4/6阻害薬abemaciclibはリソソーム機能障害を介した空胞形成を伴う新規細胞死を誘導する (2020)
  • Author(s): 日野浩嗣、風間宏美、森谷昇太、高野直治、平本正樹、宮澤啓介
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] CDK4/6阻害薬abemaciclibはリソソームの酸性化、膨化により空胞形成を起こし、新規形式の細胞死を誘導する (2020)
  • Author(s): 日野浩嗣、入山規良、國場寛子、風間宏美、森谷昇太、高野直治、平本正樹、相澤信、宮澤啓介
  • Organizer: 第93回日本生化学会大会
• [Presentation] 阻害薬abemaciclibはリソソームの酸性化、膨化による空胞形成を伴った新規細胞死を誘導する (2020)
  • Author(s): 日野浩嗣、入山規良、國場寛子、風間宏美、森谷昇太、高野直治、平本正樹、相澤信、宮澤 啓介
  • Organizer: 第125回日本解剖学会総会・全国学術集会
• [Presentation] Development of luminescent probes for real-time detection of phosphorylation balance by CDK/PP2A in cell cycle (2019)
  • Author(s): Hino Hirotsugu, Nagai Takeharu, Takaki Kaori, Kobe Mika, Mochida Satoru
  • Organizer: The 4th Taiwan-Japan Bilateral Conference on Protein Phosphatase
  • Int'l Joint Research / Invited
• [Presentation] CDK4/6阻害薬abemaciclibのリソソームを標的とした空胞形成を伴う新規細胞死 (2019)
  • Author(s): 日野浩嗣、風間宏美、森谷昇太、高野直治、平本正樹、宮澤啓介
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] CDK4/6阻害薬abemaciclibによるリソソーム由来の空胞形成を伴った新規細胞死誘導 (2019)
  • Author(s): 日野浩嗣、入山規良、國場寛子、風間宏美、森谷昇太、高野直治、平本正樹、相澤信、宮澤 啓介
  • Organizer: 第92回日本生化学会大会
• [Presentation] CDK4/6阻害薬abemaciclibはリソソーム由来の空胞形成を伴った細胞死を誘導する (2018)
  • Author(s): 日野浩嗣、入山規良、國場寛子、風間宏美、森谷昇太、高野直治、平本正樹、宮澤 啓介
  • Organizer: 第91回日本生化学会大会
• [Presentation] CDK4/6阻害薬abemaciclibのリソソームを標的とした細胞死誘導効果 (2018)
  • Author(s): 日野浩嗣、風間宏美、森谷昇太、高野直治、平本正樹、宮澤啓介
  • Organizer: 第77回日本癌学会学術総会
• [Remarks] 日本大学研究者情報システム （日野浩嗣）
  • URL: http://kenkyu-web.cin.nihon-u.ac.jp/Profiles/159/0015841/profile.html
• [Remarks] 日本大学 研究者情報システム
  • URL: https://kenkyu-web.cin.nihon-u.ac.jp/Profiles/159/0015841/profile.html