The role of TLR4 signaling pathway and exosome heat shock protein in chronic myeloid leukemia

• Project/Area Number: 23590309
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: TSUKAHARA Fujiko 東京女子医科大学, 医学部, 講師 (40119996)
• Project Period (FY): 2011-04-28 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 慢性骨髄性白血病 / 熱ショックタンパク質 / Toll様受容体 / 薬剤耐性 / LPS / 熱ショック蛋白質 / 癌 / 薬理学

Outline of Final Research Achievements

Although BCR-ABL tyrosine-kinase inhibitor (imatinib) is effective front-line therapy for chronic myeloid leukemia (CML), drug resistance is a well-recognized problem. In the present study, we found that the stimulation of TLR4 signaling pathway up-regulates BCR-ABL protein levels and may contribute to imatinib resistance. Heat shock proteins appear to be involved in the protein stability of BCR-ABL. Our findings provide new insight into the role of the TLR4 signaling pathway in drug resistance, and may have implications for the development of new therapeutic strategies to overcome drug resistance in CML.

Research Products

• [Journal Article] Drug targeting based on a new concept---Targeting against TLR4 as an example. (2015)
  • Author(s): Maru, Y, Tomita T, Deguchi A, Ieguchi K, Takita M, Tsukahara F, Takemura K, Kitao A, Gusovksy F
  • Journal Title: Endocrine, Metabolic & Immune Disorders - Drug Targets Volume: 15
  • Peer Reviewed
• [Journal Article] Nuclear export of the influenza virus ribonucleoprotein complex: Interaction of Hsc70 with viral proteins M1 and NS2 (2014)
  • Author(s): Watanabe K, Shimizu T, Noda S, Tsukahara F, Maru, Y, Kobayashi N
  • Journal Title: FEBS Open Bio Volume: 4 Issue: 1 Pages: 683-688
  • DOI: 10.1016/j.fob.2014.07.004
  • NAID: 120006986451
  • Peer Reviewed / Open Access
• [Journal Article] LPS/TLR4 signaling induces imatinib-resistance in Chronic myeloid leukemia-model cells (2014)
  • Author(s): Fujiko Tsukahara and Yoshiro Maru
  • Journal Title: Journal of Pharmacological Science Volume: 124
  • Peer Reviewed
• [Journal Article] 発癌メカニズムにおけるmTOR (2014)
  • Author(s): 塚原富士子、丸 義朗
  • Journal Title: 医学のあゆみ Volume: 248 Pages: 121-127
  • Peer Reviewed
• [Journal Article] Connexin43 Functions as a Novel Interacting Partner of Heat Shock Cognate Protein 70 (2013)
  • Author(s): Hatakeyama T, Dai P, Harada Y, Hino H, Tsukahara F, Maru Y, Otsuji E, Takamatsu T
  • Journal Title: Sci Rep Volume: 3 Issue: 1 Pages: 2719-2719
  • DOI: 10.1038/srep02719
  • Peer Reviewed
• [Journal Article] Intramolecular regulatory mechanism of degradation of chronic myeloid leukemia oncoprotein, BCR-ABL (2013)
  • Author(s): Fujiko Tsukahara and Yoshiro Maru
  • Journal Title: J Pharmacological Science Volume: 121
  • Peer Reviewed
• [Journal Article] Inhibition of immature protein sensor Bag1-mediated BCR-ABL degradation by Hsp90-cdc37chaperone (2012)
  • Author(s): Fujiko Tsukahara and Yoshiro Maru
  • Journal Title: Journal of Pharmacological Science Volume: 118
  • Peer Reviewed
• [Journal Article] p57^<Kip2> and p27^<Kip1> cooperate to maintain hematopoietic stem cell quiescence through interaction with Hsc70 (2011)
  • Author(s): Zou P, et al
  • Journal Title: Cell Stem Cell Volume: 9 Issue: 3 Pages: 247-261
  • DOI: 10.1016/j.stem.2011.07.003
  • Peer Reviewed
• [Presentation] TLR4シグナルによる慢性骨髄性白血病モデル細胞のイマチニブ耐性誘導作用 (2014)
  • Author(s): 塚原富士子、丸 義朗
  • Organizer: 第131回日本薬理学会関東部会
  • Place of Presentation: 横浜市立大学（神奈川県）
  • Year and Date: 2014-10-11
• [Presentation] TLR4 signaling induces imatinib-resistance in Chronic myeloid leukemia-model cells (2014)
  • Author(s): Tsukahara F, Maru Y
  • Organizer: 73th Annual meeting of the Japanese cancer association
  • Place of Presentation: パシフィコ横浜（神奈川県）
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] LPS/TLR4 signaling induces imatinib-resistance in Chronic myeloid leukemia-model cells (2014)
  • Author(s): Fujiko Tsukahara and Yoshiro Maru
  • Organizer: The 87th Annual Meeting of The Japanese Pharmacological Society
  • Place of Presentation: Sendai
• [Presentation] Intramolecular regulatory mechanism of degradation of chronic myeloid leukemia oncoprotein, BCR-ABL (2013)
  • Author(s): Fujiko Tsukahara and Yoshiro Maru
  • Organizer: The 86th Annual Meeting of The Japanese Pharmacological Society
  • Place of Presentation: Fukuoka
• [Presentation] PP2A promotes immature protein sensor Bag1-mediated BCR-ABL degradation (2012)
  • Author(s): Fujiko Tsukahara and Yoshiro Maru
  • Organizer: The 71st Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Sapporo
• [Presentation] Bag1 targets conformationally immature BCR-ABL for degradation
  • Author(s): Fujiko Tsukahara and Yoshiro Maru
  • Organizer: The 2nd JSH International Symposium
  • Place of Presentation: 長崎
• [Presentation] Hsp90/Cdc37 chaperones attenuate immature protein sensor Bag1-mediated BCR-ABL degradation
  • Author(s): Fujiko Tsukahara and Yoshiro Maru
  • Organizer: 70th Annual meeting of the Japanese cancer association
  • Place of Presentation: 名古屋
• [Presentation] Inhibition of immature protein sensor Bag1-mediated BCR-ABL degradation by Hsp90-cdc37chaperone
  • Author(s): Fujiko Tsukahara and Yoshiro Maru
  • Organizer: The 85th Annual meeting of the Japanese pharmacological society
  • Place of Presentation: 京都