Development of intracellular proteolytic pathways targeted therapies for the treatment of multiple myeloma

• Project/Area Number: 25860398
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Applied pharmacology
• Research Institution: Tokyo Medical University
• Principal Investigator: Moriya Shota 東京医科大学, 医学部, 助教 (30634935)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 多発性骨髄腫 / プロテアソーム / オートファジー / マクロライド / 小胞体ストレス / クラリスロマイシン / アグリソーム / ボルテゾミブ / ミエローマ / 骨髄腫 / CHOP

Outline of Final Research Achievements

The specific 26S proteasome inhibitor bortezomib (BZ) induces autophagy in myeloma (MM) cells. The macrolide antibiotics clarithromycin (CAM) blocked autophagy flux, and BZ+CAM enhanced cytotoxicity in MM cell lines. Its combination, for the simultaneous blocking of the proteasome and autophagy leads to enhanced MM cell apoptosis. As misfolded protein is recruited by histone HDAC6 to dynein motors for aggresome transport, serving to sequester misfolded proteins, we further investigated the cellular effects of targeting proteolytic pathways and aggresome formation concomitantly in MM cells. Pronounced apoptosis was induced by the combination of HDAC6 inhibitor SAHA with BZ+CAM compared with each reagent or a 2-reagent combination. BZ+CAM treatment induced aggresome formation in the perinuclear region, whereas they were inhibited in the presence of SAHA. Targeting the integrated networks of aggresome, proteasome, and autophagy is suggested to induce efficient apoptosis in MM cells.

Research Products

• [Journal Article] Cell proliferation potency is independent of FGF4 signaling in trophoblast stem cells derived from androgenetic embryos (2016)
  • Author(s): Ogawa H, Takyu R, Morimoto H, Toei S, Sakon H, Goto S, Moriya S, Kono T.
  • Journal Title: Journal of Reproduction and Development Volume: 62 Issue: 1 Pages: 51-58
  • DOI: 10.1262/jrd.2015-097
  • NAID: 130005126319
  • ISSN: 0916-8818, 1348-4400
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Macrolides sensitize EGFR-TKI-induced non-apoptotic cell death via blocking autophagy flux in pancreatic cancer cell lines. (2016)
  • Author(s): Mukai S, Moriya S, Hiramoto M, Kazama H, Kokuba H, Che XF, Yokoyama T, Sakamoto S, Sugawara A, Sunazuka T, Omura S, Handa H, Itoi T, Miyazawa K.
  • Journal Title: Int J Oncol Volume: 48 Issue: 1 Pages: 45-54
  • DOI: 10.3892/ijo.2015.3237
  • NAID: 120005845877
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Targeting the integrated networks of aggresome formation, proteasome, and autophagy potentiates ER stress-mediated cell death in multiple myeloma cells. (2015)
  • Author(s): Moriya S, Komatsu S, Yamasaki K, Kawai Y, Kokuba H, Hirota A, Che XF, Inazu M, Gotoh A, Hiramoto M, Miyazawa K
  • Journal Title: Int J Oncol. Volume: Feb;46(2) Issue: 2 Pages: 474-86
  • DOI: 10.3892/ijo.2014.2773
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] EGFR-independent autophagy induction with gefitinib and enhancement of its cytotoxic effect by targeting autophagy with clarithromycin in non-small cell lung cancer cells. (2015)
  • Author(s): Sugita S, Ito K, Yamashiro Y, Moriya S, Che XF, Yokoyama T, Hiramoto M, Miyazawa K.
  • Journal Title: Biochem Biophys Res Commun. Volume: Apr 7 Issue: 1 Pages: 28-34
  • DOI: 10.1016/j.bbrc.2015.03.162
  • Peer Reviewed / Open Access
• [Journal Article] Macrolide antibiotics block autophagy flux and sensitize to bortezomib via endoplasmic reticulum stress-mediated CHOP induction in myeloma cells (2013)
  • Author(s): Moriya S, Che XF, Komatsu S, Abe A,Kawaguchi T, Gotoh A, Inazu M, Tomoda A, Miyazawa K
  • Journal Title: Int J Oncol Volume: 42 Issue: 5 Pages: 1541-1550
  • DOI: 10.3892/ijo.2013.1870
  • Peer Reviewed
• [Journal Article] Combined treatment with SAHA, bortezomib, and clarithromycin for concomitant targeting of aggresome formation and intracellular proteolytic pathways enhances ER stress-mediated cell death in breast cancer cells. (2013)
  • Author(s): Komatsu S, Moriya S, Che XF, Yokoyama T, Kohno N, Miyazawa K.
  • Journal Title: Biochem Biophys Res Commun Volume: Jul 19;437(1) Issue: 1 Pages: 41-7
  • DOI: 10.1016/j.bbrc.2013.06.032
  • Peer Reviewed
• [Journal Article] 2-Aminophenoxazine-3-one-induced apoptosis via generation of reactive oxygen species followed by c-jun N-terminal kinase activation in the human glioblastoma cell line LN229. (2013)
  • Author(s): Che XF, Moriya S, Zheng CL, Abe A, Tomoda A, Miyazawa K.
  • Journal Title: Int J Oncol. Volume: Nov;43(5) Issue: 5 Pages: 1456-66
  • DOI: 10.3892/ijo.2013.2088
  • Peer Reviewed
• [Presentation] Macrolides Sensitize EGFR-TKI-Induced Non-Apoptotic Cell Death via Blocking Autophagy Flux in Pancreatic Cancer Cell Lines (2015)
  • Author(s): 向井俊太郎，森谷昇太，平本正樹，風間宏美，國場寛子，横山智央，半田宏，糸井隆夫，宮澤啓介
  • Organizer: 第176回東京医科大学医学会総会
  • Place of Presentation: 東京医科大学病院
  • Year and Date: 2015-11-07
• [Presentation] クラリスロマイシン併用によるゲフィチニブ誘導性オートファジーを標的とした肺癌細胞株の殺細胞効果の増強 (2015)
  • Author(s): 森谷昇太，車暁芳，横山智央，平本正樹，宮澤啓介
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-10-08
• [Presentation] Targeting the integrated networks of aggresome formation, proteasome, and autophagy potentiates ER stress‑mediated cell death in multiple myeloma cells. (2015)
  • Author(s): 森谷昇太，小松誠一郎，山﨑佳穗，河合優佑，國場寛子，車暁芳，稲津正人，後藤明彦，平本正樹，半田宏，宮澤啓介
  • Organizer: 第17５回東京医科大学医学会総会 （医学会奨励賞受賞講演）
  • Place of Presentation: 東京医科大学病院
  • Year and Date: 2015-06-07
• [Presentation] EGFR-independent autophagy induction with gefitinib and enhancement of its cytotoxic effect by targeting autophagy with clarithromycin in non-small cell lung cancer cells (2015)
  • Author(s): 伊藤謙太郎，杉田翔平，山城優太朗，森谷昇太，車暁芳，平本正樹，横山智央，宮澤啓介
  • Organizer: 第17５回東京医科大学医学会総会
  • Place of Presentation: 東京医科大学病院
  • Year and Date: 2015-06-07
• [Presentation] Targeting aggresome formation enhances ER-stress mediated cell death in myeloma cells. (2014)
  • Author(s): 森谷昇太，小松誠一郎，車暁芳，山﨑佳穗，國場寛子，廣田綾子，稲津正人，後藤明彦，宮澤啓介
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] Simultaneous targeting aggresome, proteasome, and autophagy potentiates ER-stress mediated cell death in myeloma cells (2014)
  • Author(s): 森谷昇太，小松誠一郎，車暁芳，後藤明彦，宮澤啓介
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Concomitant Targeting Intracellular Proteolytic Pathways Enhances ER-stress Mediated Cell Death in Breast Cancer Cells (2013)
  • Author(s): 小松誠一郎，森谷昇太，車暁芳，河野範男，宮澤啓介
  • Organizer: 第７２回 日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
• [Presentation] Targeting intracellular proteolytic systems enhances ER-stress mediated myel oma cell death. (2013)
  • Author(s): 森谷昇太，小松誠一郎，山﨑佳穗，車暁芳，宮澤啓介
  • Organizer: 第75回 日本血液学会学術集会
  • Place of Presentation: ロイトン札幌
• [Presentation] Targeting intracellular proteolytic pathways with bortezomib, clarithromycin, and HDAC6 inhibitor enhances ER-stress mediated cell death in myeloma cells (2013)
  • Author(s): 森谷昇太，小松誠一郎，山﨑佳穗，車暁芳，宮澤啓介
  • Organizer: 第86回 日本生化学会大会
  • Place of Presentation: パシフィコ横浜
• [Presentation] DNAメチル化阻害剤による白血病細胞のオートファジーと小胞体ストレス誘導に関する検討
  • Author(s): 宮下竜伊，石川和宏，森谷昇太，宮澤啓介
  • Organizer: 第171 回 東京医科大学医学会総会
  • Place of Presentation: 東京医科大学病院
• [Presentation] Survivin を標的とする合成ペプチドによる成人T 細胞白血病細胞（ATL）に対する新規治療法の開発
  • Author(s): 車暁芳，森谷昇太，宮澤啓介
  • Organizer: 第171 回 東京医科大学医学会総会
  • Place of Presentation: 東京医科大学病院
• [Remarks] 東京医科大学 生化学
  • URL: http://www.tokyo-med.ac.jp/faculty/med/course/course13.html