The suppression of the SPHK1/S1P/S1PR3 signaling pathway diminishes EGFR activation and increases the sensitivity of non-small cell lung cancer to gefitinib
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...
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Elsevier
2025-01-01
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| Series: | Current Research in Pharmacology and Drug Discovery |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2590257124000397 |
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| author | Jing Zhang Zequn Wang Xihua Wei Mengyuan Han Ribai Yan Lijie Ma Yan Pan |
| author_facet | Jing Zhang Zequn Wang Xihua Wei Mengyuan Han Ribai Yan Lijie Ma Yan Pan |
| author_sort | Jing Zhang |
| collection | DOAJ |
| description | 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 (IC50) 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. |
| format | Article |
| id | doaj-art-7cc58891007e4ca9b06a3a795dc8e828 |
| institution | Kabale University |
| issn | 2590-2571 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Current Research in Pharmacology and Drug Discovery |
| spelling | doaj-art-7cc58891007e4ca9b06a3a795dc8e8282025-01-19T06:26:38ZengElsevierCurrent Research in Pharmacology and Drug Discovery2590-25712025-01-018100212The suppression of the SPHK1/S1P/S1PR3 signaling pathway diminishes EGFR activation and increases the sensitivity of non-small cell lung cancer to gefitinibJing Zhang0Zequn Wang1Xihua Wei2Mengyuan Han3Ribai Yan4Lijie Ma5Yan Pan6Inner Mongolia Key Laboratory of Molecular Biology, Inner Mongolia Medical University, Hohhot 010059, ChinaDepartment of Pharmacology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing 100191, ChinaDepartment of Pharmacology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing 100191, ChinaDepartment of Pharmacology, Xinjiang Medical University, Urumqi, Xinjiang 830011, ChinaSchool of Pharmaceutical Sciences, Peking University, Beijing 100191, China; Correspondence author.Inner Mongolia Key Laboratory of Molecular Biology, Inner Mongolia Medical University, Hohhot 010059, China; Corresponding author.Department of Pharmacology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing 100191, China; Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing 100191, China; Corresponding author. Department of Pharmacology, School of Basic Medical Sciences, Health Science Center, Peking University, Beijing 100191, China.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 (IC50) 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.http://www.sciencedirect.com/science/article/pii/S2590257124000397Sphingosine kinase 1Sphingosine-1-phosphateSphingosine 1-phosphate receptorGefitinibNon-small-cell lung cancer |
| spellingShingle | Jing Zhang Zequn Wang Xihua Wei Mengyuan Han Ribai Yan Lijie Ma Yan Pan The suppression of the SPHK1/S1P/S1PR3 signaling pathway diminishes EGFR activation and increases the sensitivity of non-small cell lung cancer to gefitinib Current Research in Pharmacology and Drug Discovery Sphingosine kinase 1 Sphingosine-1-phosphate Sphingosine 1-phosphate receptor Gefitinib Non-small-cell lung cancer |
| title | The suppression of the SPHK1/S1P/S1PR3 signaling pathway diminishes EGFR activation and increases the sensitivity of non-small cell lung cancer to gefitinib |
| title_full | The suppression of the SPHK1/S1P/S1PR3 signaling pathway diminishes EGFR activation and increases the sensitivity of non-small cell lung cancer to gefitinib |
| title_fullStr | The suppression of the SPHK1/S1P/S1PR3 signaling pathway diminishes EGFR activation and increases the sensitivity of non-small cell lung cancer to gefitinib |
| title_full_unstemmed | The suppression of the SPHK1/S1P/S1PR3 signaling pathway diminishes EGFR activation and increases the sensitivity of non-small cell lung cancer to gefitinib |
| title_short | The suppression of the SPHK1/S1P/S1PR3 signaling pathway diminishes EGFR activation and increases the sensitivity of non-small cell lung cancer to gefitinib |
| title_sort | suppression of the sphk1 s1p s1pr3 signaling pathway diminishes egfr activation and increases the sensitivity of non small cell lung cancer to gefitinib |
| topic | Sphingosine kinase 1 Sphingosine-1-phosphate Sphingosine 1-phosphate receptor Gefitinib Non-small-cell lung cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2590257124000397 |
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