Elucidation of DHA's function as a protein interaction regulatory factor

• Project/Area Number: 20H03079
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 40040:Aquatic life science-related
• Research Institution: Teikyo University of Science & Technology
• Principal Investigator: Yamada Hidetoshi 帝京科学大学, 生命環境学部, 准教授 (70511955)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2022: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2021: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2020: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: DHA / RACK1 / PKCθ / 抗がん作用 / Rack1 / PKC / 抗腫瘍増殖 / Protein kinase C / プロテインカイネースC / ドコサヘキサエン酸（DHA）

Outline of Research at the Start

ドコサヘキサエン酸（DHA）欠乏は脳機能障害や精子形成異常などを引き起こす。また、DHAには心臓・血管障害やがん転移抑制など疾病抑制効果がある。一方で、DHAがどのようなメカニズムで組織形成や疾病予防に働くのかは不明な点が多い。我々はDHAが蛋白質間相互作用の足場蛋白質のReceptor for activated C kinase 1 (Rack1)に結合し、プロテインカイネースC（PKC）を介した細胞増殖シグナルを抑制することを見出した。本研究では、DHAのRack1を介した細胞内での蛋白質間相互作用の制御について解析し、組織形成および疾病抑制におけるDHAの作用機構解明に取り組む。

Outline of Final Research Achievements

In this study, we focused on the interaction between RACK1 and the omega-3 fatty acid DHA, aiming to elucidate the anti-cancer effects of DHA. Through our research, we discovered that the inhibitory effect on the interaction between RACK1 and either PKCβ or PKCθ is a DHA-specific action among fatty acids. Furthermore, we found that DHA alters the intracellular localization of PKCθ and RACK1, the anti-tumor effect of DHA is expressed in PKCθ-expressing cells, and DHA inhibits PKC signal transduction.
These results provide a novel mechanism of action for DHA's anti-cancer effect, previously unknown, suggesting that DHA may be particularly effective in cells that undergo cell proliferation dependent on PKCθ signaling.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、DHAの抗がん作用に関する新たな作用機序を示す結果であり、脂肪酸や脂肪酸代謝物によるがんの予防や治療に関する新たな知見である。さらに、DHAがPKCθシグナル依存的に細胞増殖を行う細胞に特に有効である可能性を示唆していることから、がん治療の新たな可能性を示す研究である。

Research Products

• [Journal Article] 8(<i>R</i>)-Hydroxyeicosapentaenoic acid (8<i>R</i>-HEPE) induces transcription of cholesterol efflux receptors via activation of liver X receptor in macrophages (2023)
  • Author(s): Yamada Hidetoshi、Uemura Aiko、Miyasaka Raimu
  • Journal Title: Bioscience, Biotechnology, and Biochemistry Volume: Online ahead of print Issue: 6 Pages: 584-591
  • DOI: 10.1093/bbb/zbad025
  • Peer Reviewed
• [Presentation] ドコサヘキサエン酸(DHA)によるT細胞性白血病細胞の増殖抑制 (2023)
  • Author(s): 〇井形早希、榎本結衣、宮坂らいむ、山田秀俊
  • Organizer: 日本農芸化学会2023年度大会
• [Presentation] Docosahexaenoic acid inhibits interaction of RACK1 with PKCθ and represses melanoma and T cell leukemia cell proliferation (2022)
  • Author(s): ○Yamada H, Miyasaka R, Igata S and Uemura A.
  • Organizer: 22nd International Congress of Nutrition in Tokyo (ICN Tokyo)
  • Int'l Joint Research