Maternal and Child Health Development Research Center, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, China.
Human Resources Department, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
BMC Cancer. 2024 Aug 8;24(1):983. doi: 10.1186/s12885-024-12742-4.
Colorectal cancer (CRC) is one of the top five cancer-related causes of mortality globally. Acquired resistance has hindered the effectiveness of 5-fluorouracil (5-FU), the main chemotherapeutic drug used to treat CRC. Sphingosine kinase 2 (SphK2) may be a cancer treatment target and involved in 5-FU resistance.
Cell growth was examined using MTT and clone formation assays for SphK2 expression. To identify immune cells in mice, flow cytometry was performed. West blotting demonstrated alterations in cell division and inflammation-related proteins. SphK2 levels and inflammation-related variables were studied using Elisa.
Due to SphK2 overexpression, immunosuppression, and 5-FU resistance are caused by the development of myeloid-derived suppressor cells (MDSCs) subsequent to IL-6/STAT3 activation and alterations in the arginase (ARG-1) protein. After therapy, the combination of SphK2 inhibitors and 5-FU can effectively suppress MDSCs while increasing CD4 and CD8 T cell infiltration into the tumor microenvironment, lowering tumor burden, and exhibiting a therapeutic impact on CRC.
Our findings suggest that 5-FU treatment combined with simultaneous Spkh2 inhibition by ABC294640 has anti-tumor synergistic effects by influencing multiple effects on tumor cells, T cells, and MDSCs, potentially improving the poor prognosis of colorectal cancer patients.
结直肠癌（CRC）是全球导致死亡的五大癌症相关原因之一。获得性耐药性阻碍了 5-氟尿嘧啶（5-FU）的有效性，5-FU 是用于治疗 CRC 的主要化疗药物。鞘氨醇激酶 2（SphK2）可能是癌症治疗的靶点，并参与 5-FU 耐药性。
通过 MTT 和克隆形成试验检测 SphK2 表达的细胞生长情况。为了鉴定小鼠中的免疫细胞，进行了流式细胞术分析。Western blot 显示细胞分裂和炎症相关蛋白的变化。使用 ELISA 研究 SphK2 水平和炎症相关变量。
由于 SphK2 的过表达，IL-6/STAT3 激活后髓系来源的抑制细胞（MDSCs）的发展导致免疫抑制和 5-FU 耐药，以及精氨酸酶（ARG-1）蛋白的改变。治疗后，SphK2 抑制剂和 5-FU 的联合治疗可以有效抑制 MDSCs，同时增加 CD4 和 CD8 T 细胞浸润肿瘤微环境，降低肿瘤负担，并对 CRC 产生治疗影响。
我们的研究结果表明，5-FU 联合 ABC294640 同时抑制 Spkh2 通过对肿瘤细胞、T 细胞和 MDSCs 的多种影响产生协同抗肿瘤作用，可能改善结直肠癌患者的不良预后。
