Abstract
The sphingosine-1-phosphate (S1P) transporter Spns2 regulates myocardial precursor migration in zebrafish and lymphocyte trafficking in mice. However, its function in cancer has not been investigated. We show here that ectopic Spns2 expression induced apoptosis and its knockdown enhanced cell migration in non-small cell lung cancer (NSCLC) cells. Metabolically, Spns2 expression increased the extracellular S1P level while its knockdown the intracellular. Pharmacological inhibition of S1P synthesis abolished the augmented cell migration mediated by Spns2 knockdown, indicating that intracellular S1P plays a key role in this process. Cell signaling studies indicated that Spns2 expression impaired GSK-3β and Stat3 mediated pro-survival pathways. Conversely, these pathways were activated by Spns2 knockdown, which explains the increased cell migration since they are also crucial for migration. Alterations of Spns2 were found to affect several enzymes involved in S1P metabolism, including sphingosine kinases, S1P phosphatases, and S1P lyase 1. Genetically, Spns2 mRNA level was found to be reduced in advanced lung cancer (LC) patients as quantified by using a small scale qPCR array. These data show for the first time that Spns2 plays key roles in regulating the cellular functions in NSCLC cells, and that its down-regulation is a potential risk factor for LC.
Highlights
Lung cancer (LC) is the leading cause of cancer related death in the United States and worldwide [1,2]
Lipidomics data showed that the S1P level in the culture medium was increased by 5.660.55 fold (Fig. 1C), consistent with previous reports [29,31,32,33,34] and confirming that the transfected spinster homolog 2 (Spns2) was fully functional
lung cancer (LC) was chosen as our focus for several reasons: 1) Spns2 is most abundantly expressed in the lung; 2) lung S1P level is increased when Spns2 is knockout in mice; and 3) S1P has been implicated as an early risk factor for LC in an epidemiology study [21,27,33]
Summary
Lung cancer (LC) is the leading cause of cancer related death in the United States and worldwide [1,2]. Genetic abnormalities have linked multiple genes and signaling pathways to NSCLC, including epidermal growth factor receptor (EGFR) family, signal transducer and activator of transcription 3 (Stat3), and phosphoinositide 3-kinase–Akt–mTOR pathways [1,2,4]. These discoveries have led to uniquely targeted therapies with specific inhibitor drugs such as erlotinib and gefitinib for mutations in EGFR [5] or crizotinib for gene translocation resulting in the EML4-ALK oncogene [6]. A deeper understanding of the origins and the molecular mechanisms of metastasis of the disease is urgently needed in order to improve prevention and treatment
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