Elucidation of the ASK family-regulated mechanism of cancer metastasis and search for inhibitors

• Project/Area Number: 18K19469
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Ichijo Hidenori 東京大学, 大学院薬学系研究科(薬学部), 教授 (00242206)
• Project Period (FY): 2018-06-29 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: ASKファミリー / がん転移 / 阻害剤スクリーニング

Outline of Final Research Achievements

For project (A), we analyzed the phenotypes of knockout (KO) mice of Apoptosis signal-regulating kinase (ASK) family in the experimental metastasis model and revealed that attenuation of lung metastasis is specific to ASK1 KO mice, but not ASK2 KO or ASK3 KO mice. For project (B), we examined the side effects of inhibiting ASK family in endothelial cells (ECs) and revealed that ASK1 inhibition in ECs leads to contradictory phenotypes between in vivo and in vitro. Thus we concluded that ASK1 inhibition in ECs needs cautious investigation. For project (C), we decided to use anti-tumor natural killer (NK) cell-specific cre-expressing mice for in vivo screening of ASK family inhibitors.

Academic Significance and Societal Importance of the Research Achievements

申請者らはASKファミリーの長年の解析を通して得た知見を元に、ASK1ががん転移を多面的に制御することを明らかにしてきた。本研究はASKファミリーの阻害標的としての有用性の網羅的かつ統合的な解析と、in vitroとin vivo双方の阻害剤スクリーニングを提案した。がん転移治療法確立や阻害剤の開発が進まない一因として、がん細胞が最終的に転移巣を形成する確率が低く、in vivoでの阻害剤の評価が困難であることが挙げられる。本研究はASKファミリー分子に焦点を当て、新規がん転移阻害剤の探索を目的としており、がん転移の治療法確立に向けた基礎的研究として学術的及び社会的に大きな意義を持つ。

Research Products

• [Journal Article] Genome-wide siRNA screening reveals that DCAF4-mediated ubiquitination of optineurin stimulates autophagic degradation of Cu/Zn superoxide dismutase. (2020)
  • Author(s): Homma, K., Takahashi, H., Tsuburaya, N., Naguro, I., Fujisawa, T. and Ichijo, H.
  • Journal Title: J. Biol. Chem. Volume: 295 Issue: 10 Pages: 3148-3158
  • DOI: 10.1074/jbc.ra119.010239
  • Peer Reviewed / Open Access
• [Journal Article] ER-resident sensor PERK is essential for mitochondrial thermogenesis in brown adipose tissue. (2020)
  • Author(s): Kato H, Okabe K, Miyake M, Hattori K, Fukaya T, Tanimoto K, Beini S, Mizuguchi M, Torii S, Arakawa S, Ono M, Saito Y, Sugiyama T, Funatsu T, Sato K, Shimizu S, Oyadomari S, Ichijo H, Kadowaki H, Nishitoh H.
  • Journal Title: Life science alliance Volume: 3 Issue: 3 Pages: 201900576-201900576
  • DOI: 10.26508/lsa.201900576
  • NAID: 120006980545
  • Peer Reviewed / Open Access
• [Journal Article] ASK1 promotes uterine inflammation leading to pathological preterm birth (2020)
  • Author(s): Yoshikawa Midori、Iriyama Takayuki、Suzuki Kensuke、Sayama Seisuke、Tsuruga Tetsushi、Kumasawa Keiichi、Nagamatsu Takeshi、Homma Kengo、Naguro Isao、Osuga Yutaka、Ichijo Hidenori、Fujii Tomoyuki
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 1887-1887
  • DOI: 10.1038/s41598-020-58653-9
  • Peer Reviewed / Open Access
• [Journal Article] The mitochondrial protein PGAM5 suppresses energy consumption in brown adipocytes by repressing expression of uncoupling protein 1. (2020)
  • Author(s): Sugawara, S., Kanamaru, Y., Sekine, S., Maekawa, L., Takahashi, A., Yamamoto, T., Watanabe, K., Fujisawa, T., Hattori, K. and Ichijo, H.
  • Journal Title: J. Biol. Chem. Volume: 295 Issue: 17 Pages: 5588-5601
  • DOI: 10.1074/jbc.ra119.011508
  • Peer Reviewed / Open Access
• [Journal Article] Iron homeostasis and iron-regulated ROS in cell death, senescence and human diseases. (2019)
  • Author(s): Nakamura, T., Naguro, I. and Ichijo, H.
  • Journal Title: Biochim. Biophys. Acta. Gen. Subj. Volume: pii Issue: 9 Pages: 1398-1409
  • DOI: 10.1016/j.bbagen.2019.06.010
  • Peer Reviewed
• [Journal Article] Cell volume regulation in cancer cell migration driven by osmotic water flow (2019)
  • Author(s): Morishita Kazuhiro、Watanabe Kengo、Ichijo Hidenori
  • Journal Title: Cancer Science Volume: 110 Issue: 8 Pages: 2337-2347
  • DOI: 10.1111/cas.14079
  • Peer Reviewed / Open Access
• [Journal Article] β-TrCP-dependent degradation of ASK1 suppresses the induction of the apoptotic response by oxidative stress (2018)
  • Author(s): Cheng Ran、Takeda Kohsuke、Naguro Isao、Hatta Tomohisa、Iemura Shun-ichiro、Natsume Tohru、Ichijo Hidenori、Hattori Kazuki
  • Journal Title: Biochimica et Biophysica Acta (BBA) - General Subjects Volume: 1862 Issue: 10 Pages: 2271-2280
  • DOI: 10.1016/j.bbagen.2018.07.015
  • Peer Reviewed
• [Journal Article] A small-molecule inhibitor of SOD1-Derlin-1 interaction ameliorates pathology in an ALS mouse model (2018)
  • Author(s): Tsuburaya, N., Homma, K., Higuchi, T., Balia, A., Yamakoshi, H., Shibata, N., Nakamura, S., Nakagawa, H., Ikeda, S., Umezawa, N., Kato, N., Yokoshima, S., Shibuya, M., Shimonishi, M., Kojima, H., Okabe, T., Nagano, T., Naguro, I., Imamura, K., Inoue, H., Fujisawa, T., and Ichijo, H.
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 2668-2668
  • DOI: 10.1038/s41467-018-05127-2
  • NAID: 120006546002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cryo-EM structure of the volume-regulated anion channel LRRC8 (2018)
  • Author(s): Kasuya Go、Nakane Takanori、Yokoyama Takeshi、Jia Yanyan、Inoue Masato、Watanabe Kengo、Nakamura Ryoki、Nishizawa Tomohiro、Kusakizako Tsukasa、Tsutsumi Akihisa、Yanagisawa Haruaki、Dohmae Naoshi、Hattori Motoyuki、Ichijo Hidenori、Yan Zhiqiang、Kikkawa Masahide、Shirouzu Mikako、Ishitani Ryuichiro、Nureki Osamu
  • Journal Title: Nat. Struct. Mol. Biol. Volume: 25 Pages: 797-804
  • DOI: 10.1101/331207
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] ASK family kinases mediate cellular stress and redox signaling to circadian clock (2018)
  • Author(s): Imamura Kiyomichi、Yoshitane Hikari、Hattori Kazuki、Yamaguchi Mitsuo、Yoshida Kento、Okubo Takenori、Naguro Isao、Ichijo Hidenori、Fukada Yoshitaka
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 115 Issue: 14 Pages: 3646-3651
  • DOI: 10.1073/pnas.1719298115
  • Peer Reviewed / Open Access
• [Journal Article] A PP6-ASK3 Module Coordinates the Bidirectional Cell Volume Regulation under Osmotic Stress (2018)
  • Author(s): Watanabe Kengo、Umeda Tsuyoshi、Niwa Kuniyoshi、Naguro Isao、Ichijo Hidenori
  • Journal Title: Cell Reports Volume: 22 Issue: 11 Pages: 2809-2817
  • DOI: 10.1016/j.celrep.2018.02.045
  • Peer Reviewed / Open Access
• [Journal Article] Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. (2018)
  • Author(s): Galluzzi, L. et al.
  • Journal Title: Cell Death Differ. Volume: 25 Issue: 3 Pages: 486-541
  • DOI: 10.1038/s41418-017-0012-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] mASKing cancer cells in a tumor microenvironment (2018)
  • Author(s): Kamiyama Miki、Naguro, Isao、Ichijo Hidenori
  • Journal Title: Cell Cycle Volume: 17 Issue: 2 Pages: 139-140
  • DOI: 10.1080/15384101.2017.1407402
  • Peer Reviewed / Open Access
• [Journal Article] Apoptosis signal-regulating kinase 1 in regulated necrosis (2018)
  • Author(s): Hattori Kazuki、Ichijo Hidenori
  • Journal Title: Cell Cycle Volume: 17 Issue: 1 Pages: 5-6
  • DOI: 10.1080/15384101.2017.1397330
  • Peer Reviewed / Open Access
• [Journal Article] Role of ASK1/p38 Cascade in a Mouse Model of Alzheimer’s Disease and Brain Aging (2017)
  • Author(s): Hasegawa Yu、Toyama Kensuke、Uekawa Ken、Ichijo Hidenori、Kim-Mitsuyama Shokei
  • Journal Title: Journal of Alzheimer's Disease Volume: 61 Issue: 1 Pages: 259-263
  • DOI: 10.3233/jad-170645
  • Peer Reviewed / Open Access
• [Presentation] ASK1はアシアロGM1陽性細胞を介してがん転移を負に制御する (2019)
  • Author(s): 藤本磨琴,神山美樹,名黒功,一條秀憲
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] ASK1はNK細胞依存的にがん転移を制御する (2019)
  • Author(s): 藤本磨琴,神山美樹,名黒功,一條秀憲
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] 血小板におけるASK1がADP受容体P2Y12のリン酸化を介して肺へのがん転移を制御する (2018)
  • Author(s): 神山美樹, 大亀美桜, 名黒功, 一條秀憲
  • Organizer: 第22回日本がん分子標的治療学会学術集会
• [Presentation] 血管内皮細胞におけるASK1が肺へのがん転移を制御する (2018)
  • Author(s): 古川夏輝, 神山美樹, 名黒功, 一條秀憲
  • Organizer: 第22回日本がん分子標的治療学会学術集会
• [Presentation] 抗腫瘍性免疫におけるASK1の機能解析, (2018)
  • Author(s): 藤本磨琴, 神山美樹, 名黒功, 一條秀憲,
  • Organizer: 第22回日本がん分子標的治療学会学術集会
• [Presentation] Functional analysis of ASK family in hemostasis and tumor metastasis (2018)
  • Author(s): Kamiyama, M., Naguro, I., Ichijo, H.
  • Organizer: 第40回日本血栓止血学会学術集会
• [Presentation] マウスを用いたがん転移におけるASKファミリーの機能解析 (2018)
  • Author(s): 神山美樹
  • Organizer: 第27回日本がん転移学会学術集会
• [Presentation] 血管内皮細胞におけるASK1が肺へのがん転移を制御する (2018)
  • Author(s): 古川夏輝, 神山美樹, 名黒功, 一條秀憲
  • Organizer: 第91回日本生化学会大会
• [Presentation] 抗腫瘍性免疫におけるASK1の機能解析 (2018)
  • Author(s): 藤本磨琴, 神山美樹, 名黒功, 一條秀憲
  • Organizer: 第91回日本生化学会大会