The study of the mechanism by which anti-cancer drugs induce EMT

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K05732
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 37020:Chemistry and chemical methodology of biomolecules-related
• Research Institution: Showa Pharmaceutical University
• Principal Investigator: Tashiro Etsu 昭和薬科大学, 薬学部, 准教授 (00365446)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 制がん剤耐性 / EMT / TGF-b

Outline of Final Research Achievements

We found that long-term exposure of colorectal cancer LoVo cells to the platinum anticancer drug cisplatin changed the epithelial-like phenotype to the mesenchymal-like phenotype which is a typical feature of EMT (Epithelial-Mesenchymal Transition). Therefore, we tried to examine the mechanism using a chemical genomics approach, and we found that TGF-b receptor inhibitors reversed the mesenchymal phenotype of cisplatin-resistant cells to epithelial phenotypes. These results suggested that the activation of TGF-b signaling plays a critical role in the acquisition of cisplatin-induced drug resistance. Moreover, we found that cisplatin enhanced the secretion of TGF-b into the culture medium. Taken together, it is suggested that cisplatin enhances the secretion of TGF-b, which resulted in the activation of TGF-b signaling and thereby inducing EMT and subsequent drug resistance.

Free Research Field

ケミカルバイオロジー

Academic Significance and Societal Importance of the Research Achievements

制がん剤を暴露し続けると制がん剤耐性を獲得することは古くから知られており、解決すべき問題の一つである。近年、制がん剤耐性とEMTの関連が明らかになり、申請者らが独自で行った実験でも、制がん剤耐性細胞でEMTが誘導されていることが再現できた。そしてそのメカニズムの一つとして、EMTを強力に誘導するTGF-bの分泌促進という新しいモデルを提唱できたことが本研究の学術的意義である。TGF-bシグナルの阻害剤は幾つか開発されており、それらが制がん剤耐性を獲得した実際のがん患者に応用され、効果が発揮されることを期待する。