Molecular mechanisms of activated osteoblast-induced myeloma death through mitochondrial impairment and metabolic perturbation

• Project/Area Number: 16K18420
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: The University of Tokushima
• Principal Investigator: NAKAMURA Shingen 徳島大学, 大学院医歯薬学研究部(医学系), 助教 (10511321)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: multiple myeloma / osteoblast / Pim-2 / PGC-1α / AMPK / mature osteoblast / pim-2 / PGC-1 / 成熟骨芽細胞 / ミトコンドリア / がん抑制性ニッチ / 酸性環境

Outline of Final Research Achievements

In contrast to bone marrow stromal cells or osteoclasts, mature osteoblasts (OBs) induced myeloma (MM) cell death in parallel with downregulation of the pro-survival mediator Pim-2. The Pim-2 reduction triggered the downregulation of PGC-1α, an activator of glycolysis and mitochondrial biogenesis, along with subsequent ATP reduction and phosphorylation of AMPK, a key energy sensor, in MM cells. The AMPK inhibitor dorsomorphin mitigated MM cell death in cocultures with OBs. Therefore, the prompt reduction of Pim-2 and thereby PGC-1α suppression and AMPK activation in MM cells are suggested to cause the mature OB-triggered MM cell death with energy crisis.

Research Products

• [Journal Article] Effective impairment of myeloma cells and their progenitors by hyperthermia. (2018)
  • Author(s): Hirokazu Miki, Shingen Nakamura, Asuka Oda, Hirofumi Tenshin, Jumpei Teramachi, M. Hiasa, A. Bat-Erdene, Y. Maeda, M. Oura, M. Takahashi, M. Iwasa, T. Harada, S. Fujii, K. Kurahashi, S. Yoshida, K. Kagawa, I. Endo, K. Aihara, M. Ikuo, K. Itoh, Koichiro Hayashi, Michihiro Nakamura, Masahiro Abe
  • Journal Title: Oncotarget. Volume: 9 Pages: 10307-10316
  • DOI: 10.18632/oncotarget.23121
  • NAID: 120006576960
  • Peer Reviewed
• [Journal Article] Steroid pulse therapy in patients with encephalopathy associated with severe fever with thrombocytopenia syndrome (2018)
  • Author(s): Nakamura Shingen、Azuma Momoyo、Maruhashi Tomoko、Sogabe Kimiko、Sumitani Ryohei、Uemura Munenori、Iwasa Masami、Fujii Shiro、Miki Hirokazu、Kagawa Kumiko、Hiraga Takashi、Kondo Noriyasu、Fujita Hiromi、Mahara Fumihiko、Abe Masahiro
  • Journal Title: Journal of Infection and Chemotherapy Volume: 24 Pages: 389-392
  • DOI: 10.1016/j.jiac.2017.11.004
  • NAID: 120006556288
  • Peer Reviewed
• [Journal Article] Unique anti-myeloma activity by thiazolidine-2,4-dione compounds with Pim inhibiting activity. (2018)
  • Author(s): Fujii S, Nakamura S, Oda A, Miki H, Tenshin H, Teramachi J, Hiasa M, Bat-Erdene A, Maeda Y, Oura M, Takahashi M, Iwasa M, Endo I, Yoshida S, Aihara KI, Kurahashi K, Harada T, Kagawa K, Nakao M, Sano S, Abe M.
  • Journal Title: Br J Haematol. Volume: 180(2) Pages: 246-258
  • DOI: 10.1111/bjh.15033
  • Peer Reviewed
• [Journal Article] TAK1 inhibition subverts the osteoclastogenic action of TRAIL while potentiating its antimyeloma effects (2017)
  • Author(s): Tenshin Hirofumi、Teramachi Jumpei、Tanaka Eiji、Matsumoto Toshio、Abe Masahiro (他16人中2番目）
  • Journal Title: Blood Adv. Volume: 1 Pages: 2124-2137
  • DOI: 10.1182/bloodadvances.2017008813
  • Peer Reviewed / Open Access
• [Journal Article] Multiple myeloma with high adenosine deaminase expression (2017)
  • Author(s): Shingen NAKAMURA, Hirokazu MIKI, Masami IWASA, Akishige IKEGAME,Tomoko MARUHASHI, Ryohei SUMITANI, Munenori UEMURA, Mamiko TAKAHASHI,Asuka ODA, Shiro FUJII, Kumiko KAGAWA and Masahiro ABE
  • Journal Title: International Journal of Myeloma Volume: 7 Pages: 1-5
  • NAID: 120006842039
  • Peer Reviewed
• [Journal Article] Primary CD30-positive Diffuse Large B-cell Lymphoma in the Superior Vena Cava (2017)
  • Author(s): Nakamura S, Kagawa K, Sumitani R, Uemura M, Takahashi M, Iwasa M, Fujii S, Miki H, Abe M
  • Journal Title: internal medicine Volume: 56 Pages: 2043-2047
  • NAID: 130005876447
  • Peer Reviewed
• [Journal Article] Pim-2 is a critical target for treatment of osteoclastogenesis enhanced in myeloma. (2017)
  • Author(s): Teramachi J, Hiasa M, Oda A, Harada T, Nakamura S, Amachi R, Tenshin H, Iwasa M, Fujii S, Kagawa K, Miki H, Kurahashi K, Yoshida S, Endo I, Haneji T, Matsumoto T, Abe M.
  • Journal Title: Br J Haematol. Volume: 印刷中
  • NAID: 120006549655
  • Peer Reviewed
• [Journal Article] Susceptibility to bendamustine considerably varies among myeloma cells, but is enhanced in acidic conditions (2016)
  • Author(s): Nakamura S, Miki H, Oda A, Amachi R, Teramachi J, Sogabe K, Fujino H, Maruhashi T, Fujii S, Kagawa K , Abe M
  • Journal Title: International Journal of Myeloma. Volume: 6 Pages: 7-11
  • Peer Reviewed / Open Access
• [Journal Article] A vicious cycle between acid sensing and survival signaling in myeloma cells: acid-induced epigenetic alteration. (2016)
  • Author(s): Amachi R, Hiasa M, Teramachi J, Harada T, Oda A, Nakamura S, Hanson D, Watanabe K, Fujii S, Miki H, Kagawa K, Iwasa M, Endo I, Kondo T, Yoshida S, Aihara KI, Kurahashi K, Kuroda Y, Horikawa H, Tanaka E, Matsumoto T, Abe M.
  • Journal Title: Oncotarget. Volume: 7 Pages: 70447-70461
  • NAID: 120006576954
  • Peer Reviewed / Open Access
• [Presentation] Mature osteoblasts reduce Pim-2 to cause an energy crisis in myeloma cells (2017)
  • Author(s): Shingen Nakamura, Hirokazu Miki, Hirofumi Tenshin, Keiichiro Watanabe, Jumpei Teramachi, Masahiro Hiasa, Asuka Oda, Yusaku Maeda, Masahiro Oura, Mamiko Takahashi, Masami Iwasa, Takeshi Harada, Shiro Fujii, Kumiko Kagawa, Masahiro Abe
  • Organizer: 日本血液学会
• [Presentation] Mature osteoblasts reduce Pim-2 to cause an energy crisis in myeloma cells (2017)
  • Author(s): Shingen Nakamura, Hirokazu Miki, Hirofumi Tenshin, Keiichiro Watanabe, Jumpei Teramachi, Masahiro Hiasa, Asuka Oda, Yusaku Maeda, Masahiro Oura, Mamiko Takahashi, Masami Iwasa, Takeshi Harada, Shiro Fujii, Kumiko Kagawa, Masahiro Abe
  • Organizer: 日本骨髄腫学会
• [Presentation] Osteoblast creates a non-permissive niche for myeloma (2017)
  • Author(s): Ryota Amachi, Masahiro Hiasa , Jumpei Teramachi, Asuka Oda, Ariunzaya Bat-Erdene, Hirofumi Tenshin, Keiichiro Watanabe, Shingen Nakamura, Hirokazu Miki, Kumiko Kagawa, Shiro Fujii, Eiji Tanaka , Toshio Matsumoto , Masahiro Abe
  • Organizer: IADR/AADR/CADR General Session & Exhibition
  • Int'l Joint Research
• [Presentation] Restoration of bone formation induces an energy crisis in myeloma cells (2017)
  • Author(s): Ryota Amachi, Shingen Nakamura, Hirokazu Miki, ,Hirofumi Tenshin, Keiichiro Watanabe, Jumpei Teramachi, Asuka Oda, Masami Iwasa, Shiro Fujii,Kumiko Kagawa, Masahiro Abe
  • Organizer: 日本骨髄腫学会2017
  • Place of Presentation: 日本赤十字看護大学 （東京都 渋谷区）
• [Presentation] Alteration of Pim-2 synthesis and degradation in myeloma cells by anti-myeloma agents. (2016)
  • Author(s): Shingen Nakamura, Hirokazu Miki, Ariunzaya BAT-ERDENE,Hirofumi Tenshin, Ryota Amachi, Keiichiro Watanabe, Jumpei Teramachi, Asuka Oda, Masami Iwasa, Shiro Fujii,Kumiko Kagawa, Masahiro Abe
  • Organizer: 日本血液学会総会2016
  • Place of Presentation: パシフィコ横浜(神奈川県 横浜市）
  • Year and Date: 2016-10-13
• [Presentation] Creation of a non-permissive niche for myeloma by bone formation (2016)
  • Author(s): Ryota Amachi, Jumpei Teramachi，Masahiro Hiasa，Takeshi Harada，Asuka Oda，Shingen Nakamura，Keiichiro Watanabe，Shiro Fujii，Hirokazu Miki，Kumiko Kagawa，Itsuro Endo，Eiji Tanaka，Toshio Matsumoto，Masahiro Abe
  • Organizer: 日本血液学会総会2016
  • Place of Presentation: パシフィコ横浜(神奈川県 横浜市）
  • Year and Date: 2016-10-13