Lysophosphatidic acid stimulates gastric cancer cell proliferation via ERK1-dependent upregulation of sphingosine kinase 1 transcription

Abstract 

In MKN1 gastric cancer cells, lysophosphatidic acid (LPA) upregulates expression of sphingosine kinase 1 (SphK1) and its downregulation or inhibition suppresses LPA mediated proliferation. Although LPA activates numerous signaling pathways downstream of its receptors, including extracellular-signal-regulated kinase 1/2, p38, JNK, and Akt, and the transactivation of the epidermal growth factor receptor, pharmacological and molecular approaches demonstrated that only activation of ERK1, in addition to the CCAAT/enhancer-binding protein β transcription factor, is involved in transcriptional upregulation of SphK1 by LPA. Our data implicate ERK1 as an important mediator of LPA signaling leading to upregulation of SphK1 and point to SphK1 and sphingosine-1-phosphate production as potential therapeutic targets in gastric cancer.

Abbreviations: C/EBPβ, CCAAT/enhancer-binding protein β, EGF, epidermal growth factor, EGFR, epidermal growth factor receptor, ERK1/2, extracellular-signal-regulated kinase 1/2, LPA, lysophosphatidic acid, QPCR, quantitative real-time polymerase chain reaction, siRNA, small interfering RNA, S1P, sphingosine-1-phosphate, SphK1, sphingosine kinase type 1

Keywords: Lysophosphatidic acid, Sphingosine kinase, Gastric cancer, Proliferation