title: 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.
authors.affiliation: BK21PLUS R-FIND team, College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea.
authors.forename: Hyun Ji
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: BK21PLUS R-FIND team, College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea.
authors.forename: Gyeoung Jin
authors.initials: GJ
authors.lastname: Kang
authors.affiliation: BK21PLUS R-FIND team, College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea.
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: BK21PLUS R-FIND team, College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea.
authors.forename: Mi Kyung
authors.initials: MK
authors.lastname: Park
authors.affiliation: BK21PLUS R-FIND team, College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea.
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Byun
authors.affiliation: Department of Life Sciences, College of BioNano Technology, Gachon University, Sungnam 13120, Republic of Korea.
authors.forename: Seungyoon
authors.initials: S
authors.lastname: Nam
authors.affiliation: National Cancer Center, Goyang-si, Gyeonggi-do 10408, Republic of Korea.
authors.forename: Ho
authors.initials: H
authors.lastname: Lee
authors.affiliation: BK21PLUS R-FIND team, College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea. Electronic address: uatheone@dongguk.edu.
authors.forename: Chang Hoon
authors.initials: CH
authors.lastname: Lee
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002208:Caproates / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D020868:Gene Silencing; D006801:Humans; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000503:physiopathology; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D011083:Polycyclic Compounds / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: C476600:3-(((2,2-dimethyl-1-(((2-methoxy-1-phenylethyl)amino)carbonyl)propyl)amino)carbonyl)-6-(3-methyl-4-phenylphenyl)hexanoic acid; D002208:Caproates; D005419:Flavonoids; D061965:Matrix Metalloproteinase Inhibitors; D011083:Polycyclic Compounds; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; D014633:Valine; D013110:Sphingosine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: Breast cancer; FH535; MMP3; Sphingosylphosphorylcholine; UK370106; Wnt