Analysis of lysosome in pancreatic cancer

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K16584
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Jikei University School of Medicine
• Principal Investigator: Shirai Yoshihiro 東京慈恵会医科大学, 医学部, 助教 (10785364)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 膵臓癌 / Lysosome / オートファジー / 酸性αグルコシダーゼ / 酸性さらみだーぜ

Outline of Final Research Achievements

Anticancer drug resistance in unresectable pancreatic cancer was investigated focusing on lysosomal enzymes. We used human pancreatic cancer cell line and an animal model. Microarray analysis identified a group of lysosomal enzymes whose requirements were increased by anticancer drugs. Above all, elevated levels of enzymes related to glucose and lipid metabolism such as acid α-glucosidase and acid ceramidase were observed. RNA interference was performed with these enzymes as targets, and the cell growth inhibitory effect was confirmed. Inhibition of acid α-glucosidase caused abnormal mitochondrial accumulation and cell apoptosis. Inhibition of acid ceramidase caused cell death by intracellular accumulation of ceramide and ROS. Gene therapies using an adeno virus vector were verified in a mouse model, and the tumor growth inhibitory effects were confirmed.

Free Research Field

膵臓癌

Academic Significance and Societal Importance of the Research Achievements

切除不能膵臓癌には塩酸ゲムシタビンを中心とした化学療法が適応されている。生存期間中央値は7-9カ月と予後不良であり、抗癌剤耐性を示す症例に対する新たな治療法の開発が必要である。我々は抗癌剤耐性に関与するオートファジー機構の実態であるライソゾーム酵素に着目し、抗癌剤投与によって細胞内の要求が上昇する酵素群を特定し、その酵素を阻害することで抗癌体制を改善する方法を培養細胞および動物実験モデルで明らかにした。当該研究の結果は将来的に抗癌剤耐性を改善させ、膵臓癌化学療法の奏功率を大きく改善させる可能性がある。