Development of new target therapy in osteosarcoma based on endoplasmic reticulum stress response.

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K22963
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0905:Surgery of the organs maintaining homeostasis and related fields
• Research Institution: Juntendo University
• Principal Investigator: Taisei Kurihara 順天堂大学, 医学部, 非常勤助教 (20887880)
• Project Period (FY): 2020-09-11 – 2023-03-31
• Keywords: 肉腫 / 治療標的 / 小胞体ストレス応答 / XBP1 / PERK経路

Outline of Final Research Achievements

Osteosarcoma (OS) is the most common primary malignant bone tumor. We investigated the functions of endoplasmic reticulum (ER) stress activities in OS and elucidated whether ER stress inhibitors could exert antitumor effects. We performed both siRNA and inhibitor assays focusing on IRE1α-XBP1 and PERK pathways. All OS cell lines showed resistance to PERK inhibitors. ATF4 and EIF2A inhibition by siRNA did not affect the survival of OS cell lines. IRE1α-XBP1 inhibition by toyocamycin suppressed OS cell growth and cell viability was suppressed in all OS cell lines by siRNA for XBP1. The expression of XBP1s and XBP1u in OS cell lines and OS surgical samples were confirmed using qPCR. In MG63 and U2OS, toyocamycin decreased the expression level of XBP1s induced by tunicamycin. In 143B and KHOS, stimulation by toyocamycin did not clearly change the expression level of XBP1s induced by tunicamycin. Inhibition of the IRE1α-XBP1s pathway is expected to be a new target in a subset of OS.

Free Research Field

骨軟部腫瘍

Academic Significance and Societal Importance of the Research Achievements

骨肉腫細胞株ではIRE1α－XBP1経路がストレス応答に重要な役割を果たしている可能性が示唆された。IRE1α－XBP1経路阻害剤がEwing's肉腫細胞株に加え、骨肉腫細胞株においても抗腫瘍効果を示すことが示され、難治性肉腫における新たな治療選択としての可能性が示された。また、骨肉腫臨床検体を用いた検証でも、XBP1s/XBP1uの発現傾向は細胞株と同様であり、細胞株と同様の効果が期待できる可能性が示された。
一方、同時に行った実験では滑膜肉腫細胞株では全く抗腫瘍効果を示さず、肉腫横断的な治療選択とはならなかった。