Biomolecules & Therapeutics  
Sphingosylphosphorylcholine Induces Thrombospondin-1 Secretion in MCF10A Cells via ERK2
June Hee Kang1, Hyun Ji Kim1, Mi Kyung Park1,2 and Chang Hoon Lee1,*
1College of Pharmacy, Dongguk University, Seoul 10326, 2National Cancer Center, Goyang, 10408, Republic of Korea
E-mail: uatheone@dongguk.edu
Tel: +82-31-961-5213, Fax: +82-31-961-5206
Received: October 11, 2016; Revised: December 11, 2016; Accepted: January 9, 2017; Published online: March 10, 2017.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
Sphingosylphosphorylcholine (SPC) is one of the bioactive phospholipids that has many cellular functions such as cell migration, adhesion, proliferation, angiogenesis, and Ca2+ signaling. Recent studies have reported that SPC induces invasion of breast cancer cells via matrix metalloproteinase-3 (MMP-3) secretion leading to WNT activation. Thrombospondin-1 (TSP-1) is a matricellular and calcium-binding protein that binds to a wide variety of integrin and non-integrin cell surface receptors. It regulates cell proliferation, migration, and apoptosis in inflammation, angiogenesis and neoplasia. TSP-1 promotes aggressive phenotype via epithelial mesenchymal transition (EMT). The relationship between SPC and TSP-1 is unclear. We found SPC induced EMT leading to mesenchymal morphology, decrease of E-cadherin expression and increases of N-cadherin and vimentin. SPC induced secretion of thrombospondin-1 (TSP-1) during SPC-induced EMT of various breast cancer cells. Gene silencing of TSP-1 suppressed SPC-induced EMT as well as migration and invasion of MCF10A cells. An extracellular signal-regulated kinase inhibitor, PD98059, significantly suppressed the secretion of TSP-1, expressions of N-cadherin and vimentin, and decrease of E-cadherin in MCF10A cells. ERK2 siRNA suppressed TSP-1 secretion and EMT. From online PROGgene V2, relapse free survival is low in patients having high TSP-1 expressed breast cancer. Taken together, we found that SPC induced EMT and TSP-1 secretion via ERK2 signaling pathway. These results suggests that SPC-induced TSP-1 might be a new target for suppression of metastasis of breast cancer cells.
Keywords: Sphingosylphosphorylcholine, Thrombospondin-1, Epithelial mesenchymal transition, ERK2


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