ER-stress loading therapy in refractory multiple myeloma

• Project/Area Number: 26460478
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Tokyo Medical University
• Principal Investigator: Miyazawa Keisuke 東京医科大学, 医学部, 主任教授 (50209897)
• Co-Investigator(Kenkyū-buntansha): 平本 正樹 東京医科大学, 医学部, 准教授 (70297828)
• Co-Investigator(Renkei-kenkyūsha): HANDA Hiroshi 東京医科大学, 医学部, 特任教授 (80107432)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 多発性骨髄腫 / オートファジー / プロテアソーム / 小胞体ストレス / マクロライド抗生剤 / アグリソーム / プロテアソーム阻害剤 / ボルテゾミブ / マクロライド化合物 / ヒストン脱アセチル化酵素６

Outline of Final Research Achievements

Combined treatment with bortezomib (BZ）and a macrolide for the simultaneous blocking of proteasome and autophagy pathways leads to enhanced multiple myeloma (MM) cell apoptosis induction via ER stress overloading. As misfolded protein cargo is recruited by HDAC 6 to dynein motors for aggresome transport， serving to sequester misfolded proteins, we investigated the cellular effects of targeting proteolytic pathways and aggresome concomitantly in MM cells.
Pronounced apoptosis was induced by the combination of vorinostat (SAHA; potently inhibits HDAC 6) with CA M and BZ compared with each reagent or a 2-reagent combination. CAM/BZ treatment induced vimentin positive-aggresome formation, whereas it was inhibited in the presence of SAHA. The SAHA/CAM/BZ combination treatment maximally upregulated genes related to ER stress including CHOP.
Targeting the integrated networks of aggresome, proteasome, and autophagy is suggested to induce efficient ER stress-mediated apoptosis in MM cells.

Research Products

• [Journal Article] Macrolide antibiotics exhibit cytotoxiceffect under amino acid-depleted culture condition by blocking autophagy flux in head and neck squamous cell carcinoma cell lines. (2016)
  • Author(s): Hirasawa K, Moriya S, Miyahara K, Kazama H, Hirota A, Takemura J, Abe A, Inazu M, Hiramoto M, Tsukahara K, Miyazawa K.
  • Journal Title: PLoS One Volume: 11 Issue: 12 Pages: 1848-1858
  • DOI: 10.1371/journal.pone.0164529
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Targeting bortezomib-induced aggresome formation using vinorelbine enhances the cytotoxic effect along with ER stress loading in breast cancer cell lines. (2016)
  • Author(s): Miyahara K, Kazama H, Kokuba H, Komatsu S, Hirota A, Takemura J, Hirasawa K,Moriya S, Abe A, Hiramoto M, Ishikawa T, Miyazawa K.
  • Journal Title: Int J Oncol. Volume: 49 Issue: 5 Pages: 1848-1858
  • DOI: 10.3892/ijo.2016.3673
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Specific autoantigens identified by sera obtained from mice that are immunized with testicular germ cells alone. (2016)
  • Author(s): Terayama H, Hirai S, Naito M, Qu N, Katagiri C, Nagahori K, Hayashi S, Sasaki H, Moriya S, Hiramoto M, Miyazawa K, Hatayama N, Li ZL, Sakabe K, Matsushita M, Itoh M.
  • Journal Title: Sci Rep. Volume: 18 Issue: 1 Pages: 35599-35599
  • DOI: 10.1038/srep35599
  • Peer Reviewed / Open Access
• [Journal Article] Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). (2016)
  • Author(s): Klionsky DJ, Abdelmohsen K, Abe A, Miyazawa K et al.
  • Journal Title: Autophagy Volume: 12 Pages: 1-222
  • Peer Reviewed / Int'l Joint Research
• [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] Comparative analysis of type 2 diabetes-associated SNP alleles identifies allele-specific DNA-binding proteins for the KCNQ1 locus. (2015)
  • Author(s): Hiramoto M, Udagawa H, Watanabe A, Miyazawa K, Ishibashi N, Kawaguchi M, Uebanso T, Nishimura W, Nammo T, Yasuda K.
  • Journal Title: Int J Mol Med. Volume: 36 Issue: 1 Pages: 222-2230
  • DOI: 10.3892/ijmm.2015.2203
  • Peer Reviewed / 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
• [Presentation] Macrolides enhance bortezomib-induced cytotoxicity in myeloma cells co-cultured with stroma layer. (2016)
  • Author(s): 森谷昇太 、 風間宏美、 平本正樹、 相澤信、砂塚敏明、半田 宏、宮澤啓介
  • Organizer: 第78回 日本血液学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] Macrolides enhance bortezomib-induced cytotoxicity in myeloma cells co-cultured with stroma layer (2016)
  • Author(s): Moriya S, Miyazawa K et al.
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] アミノ酸飢餓状態下で、マクロライド系抗菌薬はオートファジー阻害により頭頸部癌細胞株の細胞死を誘導する (2016)
  • Author(s): 平澤一浩 、宮原か奈、 塚原清彰、森谷昇太、平本正樹、宮澤啓介
  • Organizer: 第75回日本癌学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] ビノレルビンは乳癌細胞株に於いてアグリソーム形成を阻害することによりボルテゾミブ誘導性の細胞毒性を増強する (2016)
  • Author(s): 宮原か奈 、 森谷昇太、平澤一浩、平本正樹、小松誠一郎、石川 孝、阿部晃久、宮澤啓介
  • Organizer: 第75回日本癌学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] マクロライドとオートファジー (2016)
  • Author(s): 宮澤啓介
  • Organizer: 第23回マクロライド新作用研究会
  • Place of Presentation: 東京
  • Invited
• [Presentation] Targeting autophagy with clarithromycin enhances gefitinib-induced cell death in non-small cell lung cancer cells (2015)
  • Author(s): Ｍｏｒｉｙａ Ｓ， Che Ｘ－Ｆ， Ｙｏｋｏｙａｍａ Ｔ， Ｈｉｒａｍｏｔｏ Ｍ， Ｍｉｙａｚａｗａ Ｋ
  • 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] ビタミンＫ２の抗腫瘍効果とその臨床応用の可能性 (2015)
  • Author(s): 宮澤啓介
  • Organizer: 第25回日本産婦人科学会・新生児血液学会学術集会・第18回ビタミンＫフォーラム
  • Place of Presentation: 東京ＪＡ共済ビル
  • Year and Date: 2015-06-05
  • Invited
• [Presentation] 造血器腫瘍に対する細胞内タンパク質分解ネットワーク機構を標的とする新規治療法 (2014)
  • Author(s): 宮澤啓介
  • Organizer: 高齢者造血器疾患研究会
  • Place of Presentation: 東京都 新宿
  • Year and Date: 2014-11-20
  • Invited
• [Presentation] タンパク質分解系およびアグリソームを標的とした骨髄腫細胞株の殺細胞効果の増強 (2014)
  • Author(s): 森谷昇太，平本正樹，宮澤啓介，他
  • Organizer: 日本血液学会第76回学術集会
  • Place of Presentation: 大阪府 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，平本正樹，宮澤啓介，他
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 神奈川県 横浜市 パシフィコ横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Remarks] 分子標的探索センター
  • URL: http://www.tokyo-med.ac.jp/target/
• [Remarks] 東京医科大学 分子標的探索センター
  • URL: http://www.tokyo-med.ac.jp/target/