The molecular mechanism underlying how cancer cells acquire resistance to anti-tumor drugs through mTORC1-mediated regulation of mRNA translation

• Project/Area Number: 18K07237
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kumamoto University
• Principal Investigator: Morita Masahiro 熊本大学, 生命資源研究・支援センター, 客員准教授 (50549475)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 抗がん剤 / 抵抗性 / mRNA翻訳 / 代謝リプログラミング / mTOR阻害剤 / ミトコンドリア / 肝臓がん / mTORC1シグナル / がん / mTOR / mRNA translation / Drug resistance

Outline of Final Research Achievements

Current cancer therapies targeting key components of the signaling pathways fail due mostly to the emergence of mutations or activation of compensatory signaling pathways that render these drugs ineffective. Indeed, many patients display resistance to the anti-tumor drugs by activating alternative cancer-promoting pathways. The goal of my research project is to identify alternative cancer-promoting pathways that enable cancer cells resistant to anti-tumor drugs. My research demonstrated that a combination of anti-tumor drugs with chemical inhibitors targeting mRNA translational mechanisms greatly improves its therapeutic benefits for cancer that eventually becomes resistant to treatment. Overall, the proposed research program showed a strong potential to deliver a new generation of therapeutic regimens to the population of the nation.

Academic Significance and Societal Importance of the Research Achievements

本研究課題では、がん細胞がどのように抗がん剤への抵抗性を獲得するかの分子機構の一端を示すことができた。タンパク質合成やミトコンドリアの活性を抑制する化合物を抗ガン剤と併用することによって抵抗性獲得の分子機構を抑制することにより、その抗腫瘍効果を増強することができた。以上の結果により、抗がん剤治療において新たな治療戦略を提唱することができた。

Research Products

• [Int'l Joint Research] McGill University/University of Ottawa(カナダ)
• [Int'l Joint Research] Karolinska Institute(スウェーデン)
• [Int'l Joint Research] University of Texas Southwestern/University of Illinois at Chicago/Massachusetts Institute of Technology(米国)
• [Int'l Joint Research] Tunghai University(その他の国・地域)
• [Int'l Joint Research] Karolinska Institutet(スウェーデン)
• [Int'l Joint Research] McGill University/University of Ottawa(カナダ)
• [Int'l Joint Research] University of Texas Health San Antonio/University of Illinois at Chicago(米国)
• [Int'l Joint Research] McGill University(カナダ)
• [Int'l Joint Research] UT Health Science Center(米国)
• [Int'l Joint Research] Karolinska Institutet(スウェーデン)
• [Journal Article] The CCR4-NOT deadenylase complex safeguards thymic positive selection by down-regulating aberrant pro-apoptotic gene expression (2020)
  • Author(s): Ito-Kureha Taku、Miyao Takahisa、Nishijima Saori、Suzuki Toru、Koizumi Shin-ichi、Villar-Briones Alejandro、Takahashi Akinori、Akiyama Nobuko、Morita Masahiro、Naguro Isao、Ishikawa Hiroki、Ichijo Hidenori、Akiyama Taishin、Yamamoto Tadashi
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 6169-6169
  • DOI: 10.1038/s41467-020-19975-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Menin and Menin-Associated Proteins Coregulate Cancer Energy Metabolism (2020)
  • Author(s): Chou Chih-Wei、Tan Xi、Hung Chia-Nung、Lieberman Brandon、Chen Meizhen、Kusi Meena、Mitsuya Kohzoh、Lin Chun-Lin、Morita Masahiro、Liu Zhijie、Chen Chun-Liang、Huang Tim Hui-Ming
  • Journal Title: Cancers Volume: 12 Issue: 9 Pages: 2715-2715
  • DOI: 10.3390/cancers12092715
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Hepatic Choline Transport Is Inhibited During Fatty Acid-Induced Lipotoxicity and Obesity (2020)
  • Author(s): O’Dwyer Conor、Yaworski Rebecca、Katsumura Sakie、Ghorbani Peyman、Gobeil Odai Kaelan、Nunes Julia R.C.、LeBlond Nicholas D.、Sanjana Sabrin、Smith Tyler T.K.、Han Shauna、Margison Kaitlyn D.、Alain Tommy、Morita Masahiro、Fullerton Morgan D.
  • Journal Title: Hepatology Communications Volume: 4 Issue: 6 Pages: 876-889
  • DOI: 10.1002/hep4.1516
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 4E-BP-Dependent Translational Control of Irf8 Mediates Adipose Tissue Macrophage Inflammatory Response (2020)
  • Author(s): Pearl Dana、Katsumura Sakie、Amiri Mehdi、Tabatabaei Negar、Zhang Xu、Vinette Valerie、Pang Xinhe、Beug Shawn T.、Kim Sung-Hoon、Jones Laura M.、Robichaud Nathaniel、Ong Sang-Ging、Jia Jian-Jun、Ali Hamza、Tremblay Michel L.、Jaramillo Maritza、Alain Tommy、Morita Masahiro、Sonenberg Nahum、Tahmasebi Soroush
  • Journal Title: The Journal of Immunology Volume: 204 Issue: 9 Pages: 2392-2400
  • DOI: 10.4049/jimmunol.1900538
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Hepatic posttranscriptional network comprised of CCR4?NOT deadenylase and FGF21 maintains systemic metabolic homeostasis (2019)
  • Author(s): *M. Morita, N. Siddiqui, S. Katsumura, C. Rouya, O. Larsson, T. Nagashima, B. Hekmatnejad, A. Takahashi, H. Kiyonari, M. Zang, R. St-Arnaud, V. Giguere, I. Topisirovic, M. Okada-Hatakeyama, T. Yamamoto, N. Sonenberg
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 116 Issue: 16 Pages: 7973-7981
  • DOI: 10.1073/pnas.1816023116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Translational and HIF-1α-Dependent Metabolic Reprogramming Underpin Metabolic Plasticity and Responses to Kinase Inhibitors and Biguanides (2018)
  • Author(s): 2.*L. Hulea, *S.P. Gravel, *M. Morita, M. Cargnello, O. Uchenunu, Y.K. Im, C. Lehuédé, E.H. Ma, M. Leibovitch, S. McLaughlan, M.J. Blouin, M. Parisotto, V. Papavasiliou, C. Lavoie, O. Larsson, M. Ohh, et al., P. Siegel, R.G. Jones, W. Muller, J. Ursini-Siegel, J. St-Pierre, M. Pollak, I. Topisirovic
  • Journal Title: Cell Metabolism Volume: 28 Issue: 6 Pages: 817-832.e8
  • DOI: 10.1016/j.cmet.2018.09.001
  • NAID: 40022065097
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Translational control of ERK signaling through miRNA/4EHP-directed silencing (2018)
  • Author(s): 3.S.M. Jafarnejad, C. Chapat, E. Matta-Camacho, I.A. Gelbart, G.G. Hesketh, M. Arguello, A. Garzia, S.H. Kim, J. Attig, M. Shapiro, M. Morita, A. Khoutorsky, T. Alain, C. Gkogkas, N. Stern-Ginossar, T. Tuschl, A.C. Gingras, T.F. Duchaine, N. Sonenberg
  • Journal Title: eLife Volume: 7 Pages: 35034-35034
  • DOI: 10.7554/elife.35034
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Orchestrating inter-organ communication and treating metabolic syndrome by targeting mRNA decay of hepatokines (2021)
  • Author(s): Masahiro Morita
  • Organizer: Univerisity of Texas Southwestern, Hypothalamic Center WIPs
  • Invited
• [Presentation] Cross-talk between mTOR, mRNA translation, and energy metabolism in cancer (2021)
  • Author(s): Masahiro Morita
  • Organizer: University of Texas Health San Antonio, Research Discussion Seminar
  • Invited
• [Presentation] 臓器間・オルガネラ間相互作用を制御するmRNAsによるエネルギー代謝調節 (2020)
  • Author(s): 森田 斉弘
  • Organizer: 群馬大学生体調節研究所
  • Invited
• [Presentation] Cross-talk between mRNA translation and energy metabolism in cancer (2020)
  • Author(s): Masahiro Morita
  • Organizer: 43rd Annual Meeting of the Molecular Biology Society of Japan
  • Invited
• [Presentation] Post-Transcriptional Regulation of Hepatokine FGF21 in Metabolic Syndrome (2019)
  • Author(s): Masahiro Morita
  • Organizer: Department of Molecular Medicine, University of Texas Health San Antonio
  • Int'l Joint Research / Invited
• [Presentation] Translational control of mitochondria through the mTORC1/4E-BP pathway (2019)
  • Author(s): Masahiro Morita
  • Organizer: The 24th Annual Meeting of the RNA Society
  • Int'l Joint Research
• [Presentation] Translational regulation of cancer metabolism by the mTOR signaling pathway (2019)
  • Author(s): Masahiro Morita
  • Organizer: 42nd Annual Meeting of the Molecular Biology Society of Japan
  • Invited
• [Presentation] Post-Transcriptional Control of Cancer and Metabolism (mRNA translation and degradation) (2019)
  • Author(s): Masahiro Morita
  • Organizer: NASH/HCC Working Group Meeting, University of Texas Health San Antonio
  • Int'l Joint Research / Invited
• [Presentation] Translational control of mitochondrial function and dynamics through the mTORC1/4E-BP signaling pathway (2018)
  • Author(s): Masahiro Morita, Sakie Katsumura, Heidi M. McBride, John J. Bergeron, Nahum Sonenberg
  • Organizer: Cold Spring Harbor Laboratory Meeting; Translational Control
  • Int'l Joint Research
• [Presentation] Translational control of mitochondrial function and dynamics through the mTORC1/4E-BP signaling pathway (2018)
  • Author(s): Masahiro Morita
  • Organizer: The Center for iPS Cell Research and Application, Kyoto University
  • Invited
• [Presentation] Translational control of mitochondrial function and dynamics through the mTORC1/4E-BP signaling pathway (2018)
  • Author(s): Masahiro Morita, Heidi M. McBride, John J. Bergeron, Nahum Sonenberg
  • Organizer: The 41st Annual Meeting of the Molecular Biology Society of Japan
  • Invited
• [Presentation] mTORC1-dependent translational control of cancer and metabolism (2018)
  • Author(s): Masahiro Morita
  • Organizer: Department of Cell Systems & Anatomy, University of Texas Health San Antonio
  • Int'l Joint Research / Invited
• [Presentation] Systemic metabolic homeostasis is maintained via a hepatic post-transcriptional network comprising of the CCR4-NOT deadenylase and FGF21 (2018)
  • Author(s): Masahiro Morita
  • Organizer: Department of Cellular and Integrative Physiology, University of Texas Health San Antonio
  • Int'l Joint Research / Invited
• [Book] 月刊「細胞」2019年 8月号 (2019)
  • Author(s): 勝村 早恵・森田 斉弘
  • Total Pages: 6
  • Publisher: ニューサイエンス社
• [Book] 臨床免疫・アレルギー科 第72巻第5号 (2019)
  • Author(s): 勝村 早恵・森田 斉弘
  • Total Pages: 9
  • Publisher: 科学評論社
• [Remarks] Masahiro Morita - Google Scholar Citations
  • URL: https://scholar.google.com/citations?user=yFXA91UAAAAJ&hl=en
• [Remarks] ResearchGate
• [Remarks] キナーゼ阻害剤とビグアナイド系薬剤の併用による相乗的な抗がん作用の分子機構
  • URL: https://first.lifesciencedb.jp/18863