Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China.
State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China.
Eur J Pharmacol. 2023 Nov 15;959:176076. doi: 10.1016/j.ejphar.2023.176076. Epub 2023 Oct 4.
Metastasis is the leading cause of breast cancer-associated death. Lung metastasis commonly occurs in triple-negative breast cancer (TNBC) metastasis, worsening the TNBC prognosis. Considering their role in tumor progression and metastasis, tumor-associated macrophages (TAMs) are essential therapeutic targets in cancer therapy. Previous studies have demonstrated that honokiol inhibits tumor growth and progression. Here we assessed how honokiol inhibits lung metastasis of TNBC by regulating the polarization of macrophages. We found that honokiol decreased the expression of IL-13-triggered M2 markers like CD206, Arg1, and CCL2, preventing the invasion and migration ability of TNBC cells. The activation of signal transducer and activator of transcription STAT6 and STAT3 was significantly suppressed by honokiol in M2 polarized macrophages. Meanwhile, honokiol increased the expression of LPS/IFNγ-induced M1 markers such as CD11c, iNOS, and IL12 by promoting STAT1 phosphorylation. Besides, honokiol decreased both the ratio of M2/M1 macrophages and the expression of the IL-10/IL-12 gene in lung tissues, thereby inhibiting the proliferation and metastasis of murine breast cancer. Moreover, honokiol reduced the infiltration of macrophages to the lung tissue through the CCL2/CCR2 pathways. These results highlight the potential of honokiol in suppressing TNBC tumor progression and lung metastasis by regulating the polarization and recruitment of macrophages.
转移是乳腺癌相关死亡的主要原因。三阴性乳腺癌（TNBC）转移中常发生肺转移，使 TNBC 预后恶化。考虑到肿瘤进展和转移中的作用，肿瘤相关巨噬细胞（TAMs）是癌症治疗中的重要治疗靶点。先前的研究表明，厚朴酚抑制肿瘤生长和进展。在这里，我们评估了厚朴酚如何通过调节巨噬细胞的极化来抑制 TNBC 的肺转移。我们发现厚朴酚降低了 IL-13 触发的 M2 标志物的表达，如 CD206、Arg1 和 CCL2，从而阻止了 TNBC 细胞的侵袭和迁移能力。厚朴酚显著抑制了 M2 极化巨噬细胞中信号转导和转录激活因子 STAT6 和 STAT3 的激活。同时，厚朴酚通过促进 STAT1 磷酸化增加了 LPS/IFNγ诱导的 M1 标志物的表达，如 CD11c、iNOS 和 IL12。此外，厚朴酚降低了肺组织中 M2/M1 巨噬细胞的比例和 IL-10/IL-12 基因的表达，从而抑制了小鼠乳腺癌的增殖和转移。此外，厚朴酚通过 CCL2/CCR2 途径减少了巨噬细胞向肺组织的浸润。这些结果强调了厚朴酚通过调节巨噬细胞的极化和募集来抑制 TNBC 肿瘤进展和肺转移的潜力。
