Development of peptides inhibiting tumor angiogenesis and metastasis to develop novel anti-cancer drug

• Project/Area Number: 15H02503
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: University of Tsukuba
• Principal Investigator: Kanaho Yasunori 筑波大学, 医学医療系, 教授 (00214437)
• Co-Investigator(Renkei-kenkyūsha): FUJII Ikuo 大阪府立大学, 理学系研究科, 教授 (70189984) ; KITA Masaki 筑波大学, 数理物質系, 准教授 (30335012)
• Research Collaborator: FUNAKOSHI Yuji ; YAMAUCHI Yohei ; MIURA Yuki ; MIYACHI Taito ; Lin Yueh-Chen ; Van Ngo Thai Bich ; Tsai Meng-Tsz ; FUJIWARA Daisuke ; Tito Akindele ; YONEDA kozou ; YAMAGISHI kota
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥46,020,000 (Direct Cost: ¥35,400,000、Indirect Cost: ¥10,620,000); Fiscal Year 2017: ¥14,820,000 (Direct Cost: ¥11,400,000、Indirect Cost: ¥3,420,000); Fiscal Year 2016: ¥14,820,000 (Direct Cost: ¥11,400,000、Indirect Cost: ¥3,420,000); Fiscal Year 2015: ¥16,380,000 (Direct Cost: ¥12,600,000、Indirect Cost: ¥3,780,000)
• Keywords: 癌 / 腫瘍増殖 / 腫瘍血管新生 / 浸潤・転移 / シグナル伝達 / 抗癌剤 / 低分子量G蛋白質 / Arf6 / がん / 抗がん剤 / 薬理学 / 浸潤 / 浸潤仮足 / 低分子量Gタンパク質 / 転移 / GAP / GEF

Outline of Final Research Achievements

In this project, it was confirmed that the small G protein Arf6 positively regulates both tumor growth and invasion of cancer cells, and screened peptides inhibiting Arf6 activation to develop a novel anti-cancer drug. It was found that Arf6-specific GTPase-activating protein ARAP3 regulates invadopodia formation through inactivation of Arf6 in cancer cells, and that Arf6 expressed in lymphatic endothelial cells regulates tumor growth. These results demonstrate that Arf6 regulates both tumor growth and invasion/metastasis of cancer cells, and indicate that Arf6 is a candidate for developing a novel anti-cancer drug. When peptides inhibiting Arf6 activation were screened using the peptide library with about 35 amino acid residues, one peptide specifically inhibited Arf6 activation. Thus, a drug lead peptide for a novel anti-cancer drug development was successfully found.

Research Products

• [Int'l Joint Research] 国立台湾大学(台湾)
• [Journal Article] Anti-aging effects of black raspberry extract on cataract, alopecia, skin whitening, and weight loss (2018)
  • Author(s): Dan K, Takada A, Kanaho Y, Kusumi Y, Banno H
  • Journal Title: FUNCTIONAL FOODS IN HEALTH AND DISEASE Volume: 8 Pages: 17-34
  • Peer Reviewed
• [Journal Article] Machineries regulating the activity of the small GTPase Arf6 in cancer cells are potential targets for developing innovative anti-cancer drugs. (2017)
  • Author(s): Yamauchi Y, Miura Y, Kanaho Y.
  • Journal Title: Advanced Biological Regulation Volume: 63 Pages: 115-121
  • DOI: 10.1016/j.jbior.2016.10.004
  • Peer Reviewed
• [Journal Article] The small G protein Arf6 expressed in keratinocytes by HGF stimulation is a regulator for skin wound healing. (2017)
  • Author(s): Miura Y, Ngo Thai Bich V, Furuya M, Hasegawa H, Takahashi S, Katagiri N, Hongu T, Funakoshi Y, Ohbayashi N, Kanaho Y.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 46649-46649
  • DOI: 10.1038/srep46649
  • NAID: 120007129142
  • Peer Reviewed / Open Access
• [Journal Article] Rab32 subfamily small GTPases: pleiotropic Rabs in endosomal trafficking. (2017)
  • Author(s): Ohbayashi, N., Fukuda, M. and Kanaho, Y.
  • Journal Title: J. Biochem. Volume: 62 Issue: 2 Pages: 65-71
  • DOI: 10.1093/jb/mvx027
  • Peer Reviewed
• [Journal Article] Regulation of HGF-induced hepatocyte proliferation by the small GTPase Arf6 through the PIP2-producing enzyme PIP5K1A (2017)
  • Author(s): Tsai Meng-Tsz、Katagiri Naohiro、Ohbayashi Norihiko、Iwasaki Kenichi、Ohkohchi Nobuhiro、Ding Shih-Torng、Kanaho Yasunori、Funakoshi Yuji
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 9438-9438
  • DOI: 10.1038/s41598-017-09633-z
  • NAID: 120007134880
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Arf6 in lymphatic endothelial cells regulates lymphangiogenesis by controlling directional cell migration (2017)
  • Author(s): Lin Yueh-Chien、Ohbayashi Norihiko、Hongu Tsunaki、Katagiri Naohiro、Funakoshi Yuji、Lee Hsinyu、Kanaho Yasunori
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 11431-11431
  • DOI: 10.1038/s41598-017-11240-x
  • NAID: 120007134837
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ACAP3, the GTPase-activating protein specific to the small GTPase Arf6, regulates neuronal migration in the developing cerebral cortex (2017)
  • Author(s): Miura Y, Kanaho Y
  • Journal Title: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Volume: 493 Issue: 2 Pages: 1089-1094
  • DOI: 10.1016/j.bbrc.2017.09.076
  • Peer Reviewed
• [Journal Article] Machineries regulating the activity of the small GTPase Arf6 in cancer cells are potential targets for developing innovative anti-cancer drugs (2017)
  • Author(s): 3.Yamauchi Y, Miura Y, Kanaho Y.
  • Journal Title: Adv. Biol. Regul. Volume: 63 Pages: 115-121
  • Peer Reviewed
• [Journal Article] Pathological functions of the small GTPase Arf6 in cancer progression: Tumor angiogenesis and metastasis (2016)
  • Author(s): Hongu T, Yamauchi Y, Funakoshi Y, Katagiri N, Ohbayashi N, Kanaho Y
  • Journal Title: Small GTPases Volume: 0 Issue: 2 Pages: 1-7
  • DOI: 10.1080/21541248.2016.1154640
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ACAP3 regulates neurite outgrowth through its GAP activity specific to Arf6 in mouse hippocampal neurons (2016)
  • Author(s): 2.Miura Y, Hongu T, Yamauchi Y, Funakoshi Y, Katagiri N, Ohbayashi N, Kanaho Y.
  • Journal Title: Biochem. J. Volume: 473 Pages: 2591-602
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Pathological functions of the small GTPase Arf6 in cancer progression: tumor angiogenesis and metastasis (2016)
  • Author(s): Hongu T, Yamauchi Y, Funakoshi Y, Katagiri N, Ohbayashi N, Kanaho Y
  • Journal Title: Small GTPases Volume: in press
  • Peer Reviewed / Open Access
• [Journal Article] ADP-ribosylation factor 6 (Arf6) controls platelet spreading and clot retraction by affecting integrin αIIbβ3 trafficking (2016)
  • Author(s): Huang Y, Joshi S, Xiang B, Kanaho Y, Li Z, Bouchard BA, Moncman CL, Whiteheart SW
  • Journal Title: Blood Volume: 5 Issue: 11 Pages: 1459-1467
  • DOI: 10.1182/blood-2015-05-648550
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] PKN3 is the major regulator of angiogenesis and tumor metastasis in mice (2015)
  • Author(s): Mukai H, Muramatsu A, Mashud R, Kubouchi K, Tsujimoto S, Hongu T, Kanaho Y, Tsubaki M, Nishida S, Shioi G, Danno S, Mehruba M, Satoh R, Sugiura R.
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 18979-18979
  • DOI: 10.1038/srep18979
  • NAID: 120005703720
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PRMT8 as a phospholipase regulates Purkinje cell dendritic arborization and motor coordination. (2015)
  • Author(s): Kim, J.D., Park, K.E., Ishida, J., Kako, K., Hamada, J., Kani, S., Takeuchi, M., Namiki, K., Fukui, H., Fukuhara, S., Hibi, M,. Kobayashi, M., Kanaho, Y., Kasuya, Y., Mochizuki, N., Fukamizu, A.
  • Journal Title: Sci. Adv. Volume: 1 Issue: 11
  • DOI: 10.1126/sciadv.1500615
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Activation of the Small G Protein Arf6 by Dynamin2 through Guanine Nucleotide Exchange Factors in Endocytosis. (2015)
  • Author(s): Okada R, Yamauchi Y, Hongu T, Funakoshi Y, Ohbayashi N, Hasegawa H, Kanaho Y
  • Journal Title: Sci Rep Volume: 5 Issue: 1 Pages: 14919-14919
  • DOI: 10.1038/srep14919
  • NAID: 120007135937
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Physiological functions of the small GTPase Arf6 in the nervous system (2015)
  • Author(s): Akiyama M, Kanaho Y
  • Journal Title: Small GTPases Volume: 6 Issue: 3 Pages: 160-164
  • DOI: 10.1080/21541248.2015.1043041
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Arf6 regulates tumour angiogenesis and growth through HGF-induced endothelial β1 integrin recycling. (2015)
  • Author(s): Hongu T, Funakoshi Y, Fukuhara S, Suzuki T, Sakimoto S, Takakura N, Ema M, Takahashi S, Itoh S, Kato M, Hasegawa H, Mochizuki N, Kanaho Y.
  • Journal Title: Nat. Commun. Volume: 6 Issue: 1 Pages: 7925-7925
  • DOI: 10.1038/ncomms8925
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Phospholipase D1 facilitates second-phase myoblast fusion and skeletal muscle regeneration. (2015)
  • Author(s): Teng S, Stegner D, Chen Q, Hongu T, Hasegawa H, Chen L, Kanaho Y, Nieswandt B, Frohman MA, Huang P.
  • Journal Title: Mol Biol Cell Volume: 26 Issue: 3 Pages: 506-517
  • DOI: 10.1091/mbc.e14-03-0802
  • Peer Reviewed / Open Access
• [Presentation] Arf6 GTPase活性化因子ARAP3によるリン脂質代謝酵素PIP5K1A活性の負の制御は浸潤仮足形成に必須である (2017)
  • Author(s): 323.山内庸平、船越祐司、本宮綱記、三浦悠樹、山口英樹、片桐尚宏、大林典彦、金保安則
  • Organizer: 第59回日本脂質生化学会
• [Presentation] 低分子量G蛋白質Arf6の多彩な生理学的および病理学的機能 (2017)
  • Author(s): 324.金保安則
  • Organizer: 第39回日本薬学会九州支部コロキウム
  • Invited
• [Presentation] 低分子量G蛋白質Arf6を介したラッフル膜形成メカニズムの解析 (2016)
  • Author(s): 14.宮地泰人、本宮綱記、船越祐司、大林典彦、金保安則
  • Organizer: 第89回日本生化学会
  • Place of Presentation: 仙台国際センター、東北大学川内北キャンパス（宮城県仙台市）
  • Year and Date: 2016-09-25
• [Presentation] 癌細胞浸潤におけるArf6 GTPase活性化因子ARAP3の機能解析 (2016)
  • Author(s): 15.山内庸平、本宮綱記、山口英樹、船越祐司、大林典彦、金保安則
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台国際センター、東北大学川内北キャンパス（宮城県仙台市）
  • Year and Date: 2016-09-25
• [Presentation] ACAP3 regulates neurite outgrowth through its GAP activity specific to Arf6 in mouse hippocampal neurons (2016)
  • Author(s): 12.Yuki Miura, Tsunaki Hongu, Yuto Noda, Yohei Yamauchi, Yuji Funakoshi, Naohiro Katagiri, Norihiko Ohbayashi, Yasunori Kanaho
  • Organizer: Tsukuba Global Science Week 2016
  • Place of Presentation: つくば国際会議場（茨城県つくば市）
  • Year and Date: 2016-09-17
  • Int'l Joint Research
• [Presentation] The function of the small GTPases Arf6 in lymphangiogenesis (2016)
  • Author(s): 13.Yueh-Chien Lin, Norihiko Ohbayashi, Tsunaki Hongu, Yuji Funakoshi, Hsinyu Lee, Yasunori Kanaho
  • Organizer: Tsukuba Global Science Week 2016
  • Place of Presentation: つくば国際会議場（茨城県つくば市）
  • Year and Date: 2016-09-17
  • Int'l Joint Research
• [Presentation] Inactivation of the small GTPase Arf6 by the Arf6 GAP ARAP3 is critical for breast cancer cell invasion and metastasis (2016)
  • Author(s): 10.Yohei Yamauchi, Tsunaki Hongu, Hideki Yamaguchi, Yuji Funakoshi, Norihiko Ohbayashi, Yasunori Kanaho
  • Organizer: ASEB 2016 Science Research Conferences
  • Place of Presentation: Steamboat Springs Colorado, Colorado, U.S.A.
  • Year and Date: 2016-07-31
  • Int'l Joint Research
• [Presentation] Phospholipase D2 is a key molecule to suppress tumorigenesis through proliferation of CD8+ T lymphocytes (2016)
  • Author(s): 11.Ngo Thai Bich Van, Tsunaki Hongu, Yuji Funakoshi and Yasunori Kanaho
  • Organizer: ASEB 2016 Science Research Conferences
  • Place of Presentation: Steamboat Springs Colorado, Colorado, U.S.A.
  • Year and Date: 2016-07-31
  • Int'l Joint Research
• [Presentation] The Ubiquitin-specific Protease TRE17/USP6 Regulates Trafficking of Clathrin-independent Endocytic Cargo Proteins (2016)
  • Author(s): 7.Yuji Funakoshi, Julie G Donaldson, Yasunori Kanaho
  • Organizer: The 9th KOREA-JAPAN Conference on Cellular Signaling for Young Scientists
  • Place of Presentation: Ewha Womans University, Seoul, Korea
  • Year and Date: 2016-07-21
  • Int'l Joint Research
• [Presentation] ACAP3 regulates neurite outgrowth through its GAP activity specific to Arf6 in mouse hippocampal neurons (2016)
  • Author(s): 8.Yuki Miura, Tsunaki Hongu, Yohei Yamauchi, Yuji Funakoshi, Naohiro Katagiri, Norihiko Ohbayashi, Yasunori Kanaho
  • Organizer: The 9th KOREA-JAPAN Conference on Cellular Signaling for Young Scientists
  • Place of Presentation: Ewha Womans University, Seoul, Korea
  • Year and Date: 2016-07-21
  • Int'l Joint Research
• [Presentation] The Arf6 GTPase activating protein ARAP3 regulates breast cancer cell invasion (2016)
  • Author(s): 9.Yohei Yamauchi, Tsunaki Hongu, Hideki Yamaguchi, Yuji Funakoshi, Norihiko Ohbayashi, Yasunori Kanaho
  • Organizer: The 9th KOREA-JAPAN Conference on Cellular Signaling for Young Scientists
  • Place of Presentation: Ewha Womans University, Seoul, Korea
  • Year and Date: 2016-07-21
  • Int'l Joint Research
• [Presentation] Functional analysis of the small GTPase ADP-ribosylation factor 6 (Arf6) in skin wound healing (2016)
  • Author(s): 5.Yuki Miura, Hiroshi Hasegawa, Momoko Furuya, Naohiro Katagiri, Tsunaki Hongu, Yuji Funakoshi, Norihiko Ohbayashi, Yasunori Kanaho
  • Organizer: 第15回生命科学研究会
  • Place of Presentation: メルパルク東京（東京都港区）
  • Year and Date: 2016-06-24
• [Presentation] Arf6 GTPase活性化因子ARAP3は癌細胞浸潤・転移を制御する (2016)
  • Author(s): 6.山内庸平、本宮綱記、山口英樹、船越祐司、大林典彦、金保安則
  • Organizer: 第15回生命科学研究会
  • Place of Presentation: メルパルク東京（東京都港区）
  • Year and Date: 2016-06-24
• [Presentation] ACAP3 regulates neurite outgrowth through its GAP activity specific to Arf6 in mouse hippocampal neurons (2016)
  • Author(s): 3.Yuki Miura, Tsunaki Hongu, Naohiro Katagiri, Yuji Funakoshi, Norihiko Ohbayashi, Yasunori Kanaho
  • Organizer: 第68回日本細胞生物学会大会
  • Place of Presentation: 京都テルサ（京都府京都市）
  • Year and Date: 2016-06-15
• [Presentation] 癌細胞浸潤におけるArf6 GTPase活性化因子ARAP3の機能解析 (2016)
  • Author(s): 4.山内庸平、本宮綱記、山口英樹、船越祐司、大林典彦、金保安則
  • Organizer: 第68回日本細胞生物学会大会
  • Place of Presentation: 京都テルサ（京都府京都市）
  • Year and Date: 2016-06-15
• [Presentation] Phospholipase D2 is a key molecule to suppress tumorigenesis by regulating proliferation of CD8+ T lymphocytes (2016)
  • Author(s): 1.Ngo Thai Bich Van, Tsunaki Hongu, Yuji Funakoshi and Yasunori Kanaho
  • Organizer: 第58回脂質生化学会
  • Place of Presentation: 秋田市にぎわい交流会館AU（秋田県秋田市）
  • Year and Date: 2016-06-09
• [Presentation] The Small GTPase Arf6 regulates hepatocyte growth factor (HGF)-dependent cell proliferation through PIP2-producing enzyme PIP5Kα in hepatocytes (2016)
  • Author(s): 2.Meng-Tsz Tsai, Yuji Funakoshi, Shih-Torng Ding, Yasunori Kanaho
  • Organizer: 第58回脂質生化学会
  • Place of Presentation: 秋田市にぎわい交流会館AU（秋田県秋田市）
  • Year and Date: 2016-06-09
• [Presentation] 正中線交叉における交連軸索のSlit応答性スイッチの分子基盤：Robo1細胞内輸送系とArf6シグナリングの役割 (2015)
  • Author(s): 河田 純一, 木下ー河田 真理子, 長谷川 潤, 本宮 綱記, 柳 茂, 金保 安則, 政井 一郎, 康 東天, Yi Rao, Jane Y. Wu.
  • Organizer: BMB2015（第38回日本分子生物学会年会、第88回日本生化学会大会合同大会）
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-01
• [Presentation] ホスホリパーゼD2はCD8陽性T細胞の活性化を介して腫瘍の増大を抑制する. (2015)
  • Author(s): 金保安則、Ngo Thai Bich Van、本宮綱記、大林典彦、船越祐司
  • Organizer: BMB2015（第38回日本分子生物学会年会、第88回日本生化学会大会合同大会）
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-01
• [Presentation] 低分子量Gタンパク質Arf6による脱ユビキチン化酵素TRE17依存的リサイクリングの制御. (2015)
  • Author(s): 船越祐司、Julie G Donaldson、金保安則
  • Organizer: BMB2015（第38回日本分子生物学会年会、第88回日本生化学会大会合同大会）
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-01
• [Presentation] 癌細胞の浸潤における Arf6 GTPase 活性化因子 ARAP3 の機能解析. (2015)
  • Author(s): 山内庸平、本宮綱記、山口英樹、船越祐司、大林典彦、金保安則
  • Organizer: BMB2015 （第 38 回日本分子生物学会年会・第 88 回日本生化学会大会合同大会）
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-01
• [Presentation] The small GTPase Arf6 mediates PI3-kinase-dependent cell proliferation through PIP2-producing enzyme PIP5Kα in HGF-stimulated HepG2 cells. (2015)
  • Author(s): Meng-Tsz Tsai, Yuji Funakoshi, Shih-Torng Ding, Yasunori Kanaho
  • Organizer: BMB2015（第38回日本分子生物学会年会、第88回日本生化学会大会合同大会）
  • Place of Presentation: 神戸ポートアイランド
  • Year and Date: 2015-12-01
• [Presentation] The Arf6-specific GTPase-activating protein ARAP3 regulates breast cancer cell invasion. (2015)
  • Author(s): Yohei Yamauchi, Tsunaki Hongu, Hideki Yamaguchi, Yuji Funakoshi, Norihiko Ohbayashi, Yasunori Kanaho
  • Organizer: Tsukuba Global Science week 2015
  • Place of Presentation: つくば国際会議場
  • Year and Date: 2015-09-28
• [Presentation] The small GTPase Arf6 regulates the HGF-dependent cell proliferation through PIP2-producing enzyme PIP5Kα in HepG2 cells. (2015)
  • Author(s): Meng-Tsz Tsai, Yuji Funakoshi, Shih-Torng Ding, Yasunori Kanaho
  • Organizer: Tsukuba Global Science Week 2015
  • Place of Presentation: つくば国際会議場
  • Year and Date: 2015-09-28
• [Presentation] Phospholipase D2 as a key molecule to suppress tumorigenesis through activation of CD8+ T lymphocytes. (2015)
  • Author(s): Ngo Thai Bich Van, Tsunaki Hongu, Yuji Funakoshi and Yasunori Kanaho
  • Organizer: Tsukuba Global Science Week 2015
  • Place of Presentation: つくば国際会議場
  • Year and Date: 2015-09-28
• [Presentation] 癌細胞浸潤におけるArf6 GTPase 活性化因子ARAP3の機能解析. (2015)
  • Author(s): 山内庸平、本宮綱記、山口英樹、金保安則
  • Organizer: 第14回生命科学研究会
  • Place of Presentation: 三浦市民ホール
  • Year and Date: 2015-06-26
• [Presentation] ACAP3はArf6特異的なGAPとして働き、マウス海馬神経細胞の神経突起伸長を制御する． (2015)
  • Author(s): 三浦悠樹、本宮綱記、船越祐司、大林典彦、金保安則
  • Organizer: 第14回生命科学研究会
  • Place of Presentation: 三浦市民ホール
  • Year and Date: 2015-06-26
• [Book] 疾患モデルの作製と利用－脂質代謝異常と関連疾患 (2015)
  • Author(s): 本宮綱記、金保安則
  • Total Pages: 411
  • Publisher: 株式会社エル・アイ・シー
• [Remarks] 金保研究室 -Kanaho Lab-
• [Remarks] 金保研究室 -Kanaho Lab-
  • URL: http://www.md.tsukuba.ac.jp/basic-med/biochem/kanaholab/