Abstract
Abstract The lysophospholipids, lysophosphatidic acid (LPA) and sphingosine-1 phosphate (S1P) are important mediators of a variety of biological processes important for maintenance and progression of cancer. Autotaxin and sphingosine kinase 1 (SphK1), the enzymes responsible for synthesis of LPA and S1P, respectively, are elevated in many cancer types. We previously reported that LPA markedly enhanced SphK1 and S1P3 receptor mRNA levels, transactivated EGFR, and caused migration in MKN-1 gastric cancer cells [Shida et al., Cancer Res. 68:6569, 2008]. We have now shown that LPA potently stimulates proliferation of MKN-1 cells and downregulation of SphK1 or treatment with the isozyme-specific SphK1 inhibitor, SK1-I, markedly reduced LPA-mediated proliferation. The signaling pathways responsible for LPA-induced SphK1 upregulation were also investigated. U0126, a MEK1/2 inhibitor, completely abrogated LPA-induced elevation of SphK1 mRNA, while inhibitors of PI3K, protein kinase C, p38, JNK or NF-κB did not have an effect. Additionally, siRNA mediated downregulation of ERK2, but not AKT 1 or Akt2, blocked LPA-mediated SphK1 mRNA increase. These results were further confirmed by adenoviral expression of dominant negative MEK1, which inhibited LPA-induced SphK1 upregulation, while constitutively active MEK1 increased basal SphK1 mRNA levels. Furthermore, adenoviral expression of dominant negative or constitutively active AKT1 also did not change SphK1 mRNA levels. Our data implicate ERK2 as an important mediator of LPA signaling and upregulation of SphK1 and additionally, point to SphK1 and S1P production as potential therapeutic targets in gastric cancer. This work was supported by NCI grant R01CA61774 to SS and NIH grant 5K12HD055881 and Susan G. Komen for the Cure Research Foundation Career Catalyst Research Grant KG090510 to KT. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4103.
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