Institute of Chinese Traditional Surgery, LongHua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wanpingnan Road, Shanghai 200032, China.
Institute of Chinese Traditional Surgery, LongHua Hospital, Shanghai University of Traditional Chinese Medicine, 725 Wanpingnan Road, Shanghai 200032, China.
Int Immunopharmacol. 2023 Feb;115:109733. doi: 10.1016/j.intimp.2023.109733. Epub 2023 Jan 20.
During breast cancer development, programmed cell death 1 ligand 1 (PD-L1) overexpression in neutrophils leads to delayed apoptosis and promotes neutrophil hyperproliferation in the lung to form a premetastatic niche, which is beneficial for pulmonary metastasis. Platycodin D (PlaD), a triterpenoid saponin with known anti-inflammatory and antitumor effects, has been reported to downregulate PD-L1 expression. This study aimed to investigate the inhibitory effect of PlaD on neutrophil PD-L1 in 4 T1 tumor-bearing mice and the potential mechanism of breast cancer pulmonary metastasis. In this study, the orthotopic 4 T1 murine mammary carcinoma model was administered 10 and 20 mg/kg PlaD by gavage. PlaD reduced the excess neutrophils and decreased their high migratory capacity in bone marrow, peripheral blood and lung tissue in the premetastatic period, thereby effectively inhibiting tumor growth and pulmonary metastasis. Moreover, PlaD inhibited the phosphatidylinositol-3-kinase (PI3K)/Akt pathway by decreasing the expression of PD-L1 in neutrophils and promoted neutrophil apoptosis. In vitro, PlaD treatment decreased the viability and inhibited migration of neutrophil-like dHL-60 in a dose-dependent manner. Similarly, PlaD inhibited the increase in PD-L1 induced by IFN-γ stimulation and subsequently induced apoptosis in dHL-60 cells. In conclusion, the administration of PlaD inhibited the PI3K/Akt signaling pathway by reducing the expression of PD-L1 in neutrophils. PlaD promoted neutrophil apoptosis, thereby inhibiting the establishment of a premetastatic niche and ultimately blocking the development of pulmonary metastasis.
在乳腺癌发展过程中，中性粒细胞中程序性细胞死亡配体 1（PD-L1）的过表达导致细胞凋亡延迟，并促进肺部中性粒细胞过度增殖，形成有利于肺转移的前转移龛。已知具有抗炎和抗肿瘤作用的三萜皂苷元远志酸（PlaD）已被报道可下调 PD-L1 的表达。本研究旨在探讨 PlaD 对 4T1 荷瘤小鼠中性粒细胞 PD-L1 的抑制作用及乳腺癌肺转移的潜在机制。在这项研究中，通过灌胃给予 4T1 原位乳腺癌小鼠 10 和 20mg/kg PlaD。PlaD 减少了前转移期骨髓、外周血和肺组织中过多的中性粒细胞，并降低了其高迁移能力，从而有效抑制肿瘤生长和肺转移。此外，PlaD 通过降低中性粒细胞中 PD-L1 的表达抑制了磷脂酰肌醇-3-激酶（PI3K）/Akt 通路，并促进中性粒细胞凋亡。在体外，PlaD 处理以剂量依赖性方式降低了中性粒细胞样 dHL-60 的活力并抑制其迁移。同样，PlaD 抑制了 IFN-γ刺激诱导的 PD-L1 增加，并随后诱导 dHL-60 细胞凋亡。总之，PlaD 通过降低中性粒细胞中 PD-L1 的表达抑制了 PI3K/Akt 信号通路。PlaD 促进中性粒细胞凋亡，从而抑制前转移龛的建立，并最终阻断肺转移的发展。
