Novel effects of sphingosylphosphorylcholine on invasion of breast cancer: Involvement of matrix metalloproteinase-3 secretion leading to WNT activation

Abstract

Sphingosylphosphorylcholine (SPC) participates in several cellular processes including metastasis. SPC induces keratin reorganization and regulates the viscoelasticity of metastatic cancer cells including PANC-1 cancer cells leading to enhanced migration and invasion. The role of SPC and the relevant mechanism in invasion of breast cell are as yet unknown. SPC dose-dependently induces invasion of breast cancer cells or breast immortalized cells. Reverse transcription polymerase chain reaction and Western blot analyses of MCF10A and ZR-75-1 cells indicated that SPC induces expression and secretion of matrix metalloproteinase-3 (MMP3). From online KMPLOT, relapse free survival is high in patients having low MMP3 expressed basal breast cancer (n=581, p=0.032). UK370106 (MMP3 inhibitor) or gene silencing of MMP3 markedly inhibited the SPC-induced invasion of MCF10A cells. An extracellular signal-regulated kinase (ERK) inhibitor, PD98059, significantly suppressed the secretion and the gelatinolytic activity of MMP3, and invasion in MCF10A cells. Over-expression of ERK1 and ERK2 promoted both the expression and secretion of MMP3. In contrast, gene silencing of ERK1 and ERK2 attenuated the secretion of MMP3 in MCF10A cells. The effects of SPC-induced MMP3 secretion on β-catenin and TCF/lymphoid enhancer factor (LEF) promoter activity were examined since MMP3 indirectly activates canonical Wnt signaling. SPC induced translocation of β-catenin to nucleus and increased TCF/LEF promoter activity. These events were suppressed by UK370106 or PD98059. Wnt inhibitor, FH535 inhibited SPC-induced MMP3 secretion and invasion. Taken together, these results suggest that SPC induces MMP3 expression and secretion via ERK leading to Wnt activation.

Mammalian sphingoid bases: Biophysical, physiological and pathological properties

“…Well known examples are the sphingosylphosphorylcholine (lysosphingomyelin), galactosylsphingosine (psychosine) and glucosylsphingosine, which consist on a SO LCB linked to phosphorylcholine, galactose and glucose, respectively. Different studies suggest that these LCB derivatives have important roles in cell function [48][49][50][51][52] and might contribute to different pathologies, including cancer [53,54] and lysosomal storage diseases [55][56][57][58].…”

Molecular Characterisation of Canine Osteosarcoma in High Risk Breeds

“…MMP3 and DKK3 have been shown to have opposite effects on Wnt activation. MMP3 secretion has been shown to lead to increased Wnt activation [ 110 , 111 ], while increased DKK3 expression results in reduced Wnt activation [ 99 , 105 , 106 , 107 ]. The results presented in the current study thus appear to contradict these earlier findings, with both MMP3 and DKK3 expressed more highly in tumor compared to non-tumor tissue.…”

Sphingosylphosphorylcholine Induces Thrombospondin-1 Secretion in MCF10A Cells via ERK2

“…SPC induces invasion of MCF10A cells via secretion of MMP-3 and phosphorylation and reorganization of keratin 8. Sustained keratin phosphorylation leads to keratin loss ( Beil et al ., 2003 ; Kim et al ., 2015 , 2016 ). These results suggested that SPC might be involved in EMT.…”

“…Increased levels of SPC are found in atopic dermatitis, Niemann-Pick disease (NPD), and malignant ascites among patients with tumors ( Xiao et al ., 2001 ; Kurokawa et al ., 2009 ). SPC induces invasion via secretion of matrix metalloproteinase-3 (MMP-3) and perinuclear reorganization of keratin 8 (K8) filaments that contribute to the viscoelasticity of metastatic cancer cells ( Beil et al ., 2003 ; Kim et al ., 2015 , 2016 ).…”