HSP90 阻害剤による腫瘍関連マクロファージ分化の阻害: 乳がんの新しい治療戦略

• Published in: 日本薬理学会年会要旨集 p. 3-B-P-058
• Main Authors: 竹馬, 真理子, 洪, 羚嘉, 安井, 正人, 田中, 愛美
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2023
• Subjects: cancer; heat-shock protein; macrophage
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.97.0_3-B-P-058

Macrophages play a crucial role in regulating the innate immune system and maintain tissue homeostasis. In the tumor microenvironment, tumor-associated macrophages (TAMs) are known to promote tumor progression, mostly derived from recruiting monocytes. However, the molecular mechanism underlying the differentiation of monocytes into TAM remains unclear.This study aimed to determine the intracellular signals or target molecules involved in TAM differentiation and explore potential therapies targeting this process. First, we incubated THP-1 human monocyte cell with conditional culture medium (CM) from various breast cancer cell lines. RT-PCR analysis revealed that CM from the triple negative breast cancer cell line, MDA-MB231, significantly increased TAM markers, indicating monocyte polarization into TAMs. Next, we explored molecules inhibiting monocyte-to-TAM differentiation using the Screening Committee of Anticancer Drugs (SCADS inhibitor kit). Heat shock protein 90 (HSP90) inhibitors, ganetespib and Radicicol, were found to suppress the expression of TAM markers, suggesting that HSP90 inhibition prevented TAM differentiation. Furthermore, we sought to investigate the mechanism by which Hsp90 inhibition suppresses TAM differentiation. Western blotting showed that ganetespib blocked CM-induced activation of AKT and STAT3 pathway within 3 hours, and inhibited JAK2 pathway activation within 12 hours. These results suggested that ganetespib modulated TAM differentiation via restricting AKT pathway and JAK2/STAT3 pathway activation. The inhibitory effect of ganetespib on TAM differentiation was also confirmed in mouse breast cancer cell in vitro and murine breast cancer cell transplantation model in vivo. These findings suggest that Hsp90 inhibitors could be potential therapeutic agents for breast cancer by reducing TAM differentiation and tumor progression.