Department of Pharmacy (DIFARMA), University of Salerno, 84084 Salerno, Italy.
Anatomy and Pathology Unit, Ospedale dei Colli, AORN, "Monaldi", 84131 Naples, Italy.
Cells. 2022 Aug 15;11(16):2524. doi: 10.3390/cells11162524.
Sphingosine-1-phosphate (S1P) is involved in inflammatory signaling/s associated with the development of respiratory disorders, including cancer. However, the underlying mechanism/s are still elusive. The aim of this study was to investigate the role of S1P on circulating blood cells obtained from healthy volunteers and non-small cell lung cancer (NSCLC) patients. To pursue our goal, peripheral blood mononuclear cells (PBMCs) were isolated and stimulated with S1P. We found that the administration of S1P did not induce healthy PBMCs to release pro-inflammatory cytokines. In sharp contrast, S1P significantly increased the levels of TNF-α and IL-6 from lung cancer-derived PBMCs. This effect was S1P receptor 3 (S1PR3)-dependent. The pharmacological blockade of ceramidase and sphingosine kinases (SPHKs), key enzymes for S1P synthesis, completely reduced the release of both TNF-α and IL-6 after S1P addition on lung cancer-derived PBMCs. Interestingly, S1P-induced IL-6, but not TNF-α, release from lung cancer-derived PBMCs was mTOR- and K-Ras-dependent, while NF-κB was not involved. These data identify S1P as a bioactive lipid mediator in a chronic inflammation-driven diseases such as NSCLC. In particular, the higher presence of S1P could orchestrate the cytokine milieu in NSCLC, highlighting S1P as a pro-tumor driver.
鞘氨醇-1-磷酸（S1P）参与与呼吸疾病（包括癌症）发展相关的炎症信号转导。然而，其潜在机制仍不清楚。本研究旨在研究 S1P 对来自健康志愿者和非小细胞肺癌（NSCLC）患者的循环血细胞的作用。为了实现我们的目标，分离了外周血单核细胞（PBMC）并对其进行 S1P 刺激。我们发现，S1P 的给药并未诱导健康的 PBMC 释放促炎细胞因子。与此形成鲜明对比的是，S1P 显著增加了源自肺癌的 PBMC 中 TNF-α 和 IL-6 的水平。这种作用是 S1P 受体 3（S1PR3）依赖性的。鞘氨醇酶和鞘氨醇激酶（SPHKs）的药理学阻断，即 S1P 合成的关键酶，完全减少了 S1P 加在源自肺癌的 PBMC 上后两种细胞因子 TNF-α 和 IL-6 的释放。有趣的是，S1P 诱导源自肺癌的 PBMC 释放的 IL-6，但不是 TNF-α，依赖于 mTOR 和 K-Ras，而不依赖于 NF-κB。这些数据表明 S1P 是一种生物活性脂质介质，在 NSCLC 等慢性炎症驱动的疾病中发挥作用。特别是，S1P 的更高存在可能会协调 NSCLC 中的细胞因子环境，突出 S1P 作为一种促肿瘤驱动因子。
