Development of innovative therapies focusing on abnormalities of glycolipid metabolism, carcinogenesis mechanisms, and cancer progression in pancreatic cancer

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K16390
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Jikei University School of Medicine
• Principal Investigator: Yasuda Jungo 東京慈恵会医科大学, 医学部, 助教 (90896870)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: ライソゾーム / 酸性グルコシダーゼ / マイトファジー / ミトコンドリア膜電位 / 活性酸素 / 抗腫瘍効果 / 膵臓癌

Outline of Final Research Achievements

In pancreatic cancer, differences in enzyme activity among cancer cell lines correlated with GBA protein expression levels, and GBA knockdown caused mitochondrial dysfunction in pancreatic cancer lines, which showed an inhibitory effect on cell growth and an increase in apoptotic cells regardless of the magnitude of GBA enzyme activity. The mitophagy mechanism was searched for to evaluate the cause of this dysfunction. We induced apoptotic cells in PDAC cell lines using mdivi-1, a mitophagy inhibitor. mdivi-1 in combination with GBA knockdown significantly suppressed mitophagy compared to mdivi-1 alone.

Free Research Field

肝胆膵外科

Academic Significance and Societal Importance of the Research Achievements

ライソゾーム酵素の一つである酸性グルコシダーゼの阻害により、マイトファジーが低下し、ミトコンドリア膜電位が低下し、不良ミトコンドリアが増殖した。その結果、活性酸素の蓄積を認めアポトーシスシグナルが増強し、抗腫瘍効果が増加したため膵臓癌細胞の細胞死が誘導された。このことにより膵臓癌治療の新たな標的として有望であることがしめされた。