PDF(Pubmed)
Abstract：
OBJECTIVE: Availability of multimodal treatment strategies, including targeted therapies and immunotherapies, have improved the survival of non-small cell lung carcinoma (NSCLC). However, some patients still progress or respond poorly due to inherent resistance, acquired resistance, or lack of druggable driver mutations. Sphingosine-1-phosphate (S1P) and receptor tyrosine kinase-like orphan receptor (ROR1/2) signaling pathways are activated during lung carcinogenesis.
METHODS: In this study, we have evaluated the crosstalk of S1P and ROR1/2 signaling pathways in lung cancer cells.
RESULTS: S1P treatment of lung cancer cells decreases ROR1 and ROR2 transcript levels. While treatment with PF-543, a pharmacological SphK1 inhibitor or genetic knockdown of SPHK1 by shRNA, raises ROR1 and ROR2. Furthermore, simultaneous inhibition of SphK1 along with ROR1 reduced the migration of lung cancer cells.
CONCLUSIONS: These findings demonstrate the reciprocal regulation of both pathways, suggesting that both pathways have an inverse relation i.e, in the absence of one pathway, another pathway may take charge of the other pathway. Therefore, simultaneously targeting both pathways could serve as a potential therapeutic target for lung cancer treatment.
METHODS: In this study, we have evaluated the crosstalk of S1P and ROR1/2 signaling pathways in lung cancer cells.
RESULTS: S1P treatment of lung cancer cells decreases ROR1 and ROR2 transcript levels. While treatment with PF-543, a pharmacological SphK1 inhibitor or genetic knockdown of SPHK1 by shRNA, raises ROR1 and ROR2. Furthermore, simultaneous inhibition of SphK1 along with ROR1 reduced the migration of lung cancer cells.
CONCLUSIONS: These findings demonstrate the reciprocal regulation of both pathways, suggesting that both pathways have an inverse relation i.e, in the absence of one pathway, another pathway may take charge of the other pathway. Therefore, simultaneously targeting both pathways could serve as a potential therapeutic target for lung cancer treatment.
摘要：
目的：多模式治疗策略的可用性，包括靶向治疗和免疫疗法，改善了非小细胞肺癌（NSCLC）的生存率。然而,由于固有的抵抗力，一些患者仍然进展或反应不佳，获得性抵抗力，或者缺乏药物驱动突变。鞘氨醇-1-磷酸（S1P）和受体酪氨酸激酶样孤儿受体（ROR1/2）信号通路在肺癌发生过程中被激活。
方法：在本研究中，我们已经评估了S1P和ROR1/2信号通路在肺癌细胞中的串扰。
结果：S1P治疗肺癌细胞降低ROR1和ROR2转录水平。当用PF-543治疗时，一种药理学SphK1抑制剂或通过shRNA基因敲低SPHK1，引发ROR1和ROR2。此外，同时抑制SphK1和ROR1减少了肺癌细胞的迁移。
结论：这些发现证明了两种途径的相互调节，这表明这两种途径都有反比关系，即在没有一条途径的情况下，另一条途径可能负责另一条途径。因此,同时靶向两种途径可作为肺癌治疗的潜在治疗靶点.
方法：在本研究中，我们已经评估了S1P和ROR1/2信号通路在肺癌细胞中的串扰。
结果：S1P治疗肺癌细胞降低ROR1和ROR2转录水平。当用PF-543治疗时，一种药理学SphK1抑制剂或通过shRNA基因敲低SPHK1，引发ROR1和ROR2。此外，同时抑制SphK1和ROR1减少了肺癌细胞的迁移。
结论：这些发现证明了两种途径的相互调节，这表明这两种途径都有反比关系，即在没有一条途径的情况下，另一条途径可能负责另一条途径。因此,同时靶向两种途径可作为肺癌治疗的潜在治疗靶点.
