Zhang Jing, Wang Zequn, Wei Xihua, Han Mengyuan, Yan Ribai, Ma Lijie, Pan Yan
Inner Mongolia Key Laboratory of Molecular Biology, Inner Mongolia Medical University, Hohhot 010059, China.
Department of Pharmacology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing 100191, China.
Curr Res Pharmacol Drug Discov. 2025 Jan 9;8:100212. doi: 10.1016/j.crphar.2024.100212. eCollection 2025.
Non-small-cell lung cancer (NSCLC) represents a predominant histological subtype of lung cancer, characterized by high incidence and mortality rates. Despite significant advancements in therapeutic strategies and a deeper understanding of targeted therapies in recent years, tumor resistance remains an inevitable challenge, leading to poor prognostic outcomes. Several studies have indicated that sphingosine kinase 1 (SPHK1) plays a regulatory role in epidermal growth factor receptor (EGFR) signaling, and its elevated expression may be associated with resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Furthermore, the catalytic product of SPHK1, sphingosine 1-phosphate (S1P), along with its receptor, sphingosine 1-phosphate receptor 3 (S1PR3), plays a regulatory role in the function of the EGFR. However, the specific effects of the SPHK1/S1P/S1PR3 axis on EGFR in NSCLC, as well as the combined effects of SPHK1/S1P/S1PR3 inhibitors with the EGFR-TKI gefitinib, remain to be elucidated. In the present study, we investigated the correlation between SPHK1 expression levels and the survival rates of NSCLC patients, the relationship between SPHK1 or S1PR3 and EGFR, and the impact of SPHK1 expression on the half-maximal inhibitory concentration (IC) of gefitinib in NSCLC. In A549 cells, the phosphorylation of EGFR was significantly reduced following SPHK1 knockdown. Utilizing SPHK1/S1P/S1PR3 inhibitors, namely PF543, TY52156, and FTY720, we established that the SPHK1/S1P/S1PR3 axis modulates EGFR activation in NSCLC. Furthermore, these signaling inhibitors enhanced the anti-proliferative efficacy of the EGFR-TKI gefitinib. RNA sequencing analysis revealed substantial alterations in 85 differentially expressed genes in NSCLC cells treated with the combination of FTY720 and gefitinib. These genes were predominantly associated with pathways such as axon guidance, microRNAs in cancer, and the JAK-STAT signaling pathway, among others. Overall, targeting the SPHK1/S1P/S1PR3 signaling pathway represents a promising therapeutic strategy to enhance gefitinib sensitivity in NSCLC.
非小细胞肺癌（NSCLC）是肺癌的主要组织学亚型，具有高发病率和高死亡率的特点。尽管近年来治疗策略取得了显著进展，对靶向治疗的理解也更加深入，但肿瘤耐药性仍然是一个不可避免的挑战，导致预后不良。多项研究表明，鞘氨醇激酶1（SPHK1）在表皮生长因子受体（EGFR）信号传导中起调节作用，其表达升高可能与对EGFR酪氨酸激酶抑制剂（EGFR-TKIs）的耐药性有关。此外，SPHK1的催化产物鞘氨醇-1-磷酸（S1P）及其受体鞘氨醇-1-磷酸受体3（S1PR3）在EGFR的功能中起调节作用。然而，SPHK1/S1P/S1PR3轴在NSCLC中对EGFR的具体作用，以及SPHK1/S1P/S1PR3抑制剂与EGFR-TKI吉非替尼的联合作用仍有待阐明。在本研究中，我们调查了SPHK1表达水平与NSCLC患者生存率之间的相关性、SPHK1或S1PR3与EGFR之间的关系，以及SPHK1表达对NSCLC中吉非替尼半数抑制浓度（IC）的影响。在A549细胞中，敲低SPHK1后EGFR的磷酸化显著降低。利用SPHK1/S1P/S1PR3抑制剂，即PF543、TY52156和FTY720，我们证实SPHK1/S1P/S1PR3轴在NSCLC中调节EGFR激活。此外，这些信号抑制剂增强了EGFR-TKI吉非替尼的抗增殖功效。RNA测序分析显示，在用FTY720和吉非替尼联合处理的NSCLC细胞中，85个差异表达基因发生了显著改变。这些基因主要与轴突导向、癌症中的微小RNA以及JAK-STAT信号通路等途径相关。总体而言，靶向SPHK1/S1P/S1PR3信号通路是增强NSCLC对吉非替尼敏感性的一种有前景的治疗策略。
