Molecular basis for resistance to anti-cancer agents by cancer microenvironment and development of novel molecular-targeted agents

2022 Fiscal Year Final Research Report

• Project/Area Number: 18K06788
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: University of Miyazaki
• Principal Investigator: Ikeda Ryuji 宮崎大学, 医学部, 教授 (50398278)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Keywords: がん微小環境 / がん幹細胞 / 抗がん薬耐性

Outline of Final Research Achievements

Cancer stem-like cells (CSCs), possessing self-renewal and multipotency capabilities, are widely recognized as the underlying cause of resistance to chemotherapy and radiotherapy within the tumor microenvironment. CSCs are known to exhibit a robust efflux system, expressing multiple adenosine triphosphate-binding cassette transporters, such as P-glycoprotein and breast cancer-resistant protein. Among the inflammatory cytokines implicated in cancer development, IL-32 was found to be overexpressed in CSCs. To investigate the effects of IL-32 on chemotherapy resistance, the cisplatin-resistant cell line, KCP-4, derived from human epidermoid carcinoma KB-3-1 cells was employed. Notably, the expression of IL-32 increased in KCP-4 cells compared to that in KB-3-1 cells. Employing small interfering RNA-mediated gene silencing techniques targeting IL-32 resulted in increased sensitivity to cisplatin, suggesting a crucial role for IL-32 in chemotherapy resistance and CSC formation.

Free Research Field

医療系薬学

Academic Significance and Societal Importance of the Research Achievements

腫瘍中には、自己複製能と多分化能を有するがん幹細胞の存在することが分かってきており、がん幹細胞の存在ががんの再発や薬剤抵抗性に寄与していることが想定される。がん幹細胞の特徴の１つとして、P-糖タンパク質（P-gp）やBCRP（breast cancer-resistant protein）といったABCトランスポーターが過剰発現している。悪性腫瘍に対する抗がん薬耐性は大きな問題であり、耐性・進展の機序を解明し、実用的な治療薬を開発することは重要且つ緊急課題であると考えられる。本研究では、今回、IL-32が抗がん薬耐性因子であることを示しており、今後の治療薬の開発に貴重な情報となり得る。