title: CERS2 suppresses tumor cell invasion and is associated with decreased V-ATPase and MMP-2/MMP-9 activities in breast cancer.
abstract: Ceramide synthase 2 (CERS2) is the gene identified from a human liver cDNA library in 2001. Our previous studies have shown higher expression of CERS2 in the breast cancer patients was associated with fewer lymph node metastases. However, the molecular mechanism of CERS2 involved is unknown. Here, we found CERS2 was heterogeneously expressed in various breast cancer cells. The mRNA and protein expression levels of CERS2 in MCF7 cells, which are poorly invasive breast cancer cells, were obviously higher than that in the highly invasive cells MDA-MB-231. Results showed overexpression of CERS2 in MDA-MB-231 cells could significantly inhibit the migration and invasion ability, whereas CERS2 knockdown in MCF7 cells could significantly increase the migration and invasion ability. Overexpression of CERS2 in MDA-MB-231 cells significantly reduced the V-ATPase activity, increased the extracellular pH and decreased the pH-dependent activity of MMP-2 and MMP-9 matrix metalloproteinases (MMPs). CERS2 knockdown in MCF7 cells significantly increased the V-ATPase activity, decreased the extracellular pH and increased the activity of MMP-2 and MMP-9. Taken together, CERS2 can significantly inhibit breast cancer cell invasion and is associated with the decrease of the V-ATPase activity and extracellular hydrogen ion concentration, and in turn the activation of secreted MMP-2/MMP-9 and degradation of extracellular matrix (ECM), which ultimately suppressed tumor's invasion. Thus, CERS2 may represent a novel target for selectively disrupting V-ATPase activity and the invasive potential of cancer cells.
authors.affiliation: Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, Jiangsu, 221116, China.
authors.forename: Shao-hua
authors.initials: SH
authors.lastname: Fan
authors.forename: Yan-yan
authors.initials: YY
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: Yuan-lin
authors.initials: YL
authors.lastname: Zheng
authors.forename: Dong-mei
authors.initials: DM
authors.lastname: Wu
authors.forename: Zi-feng
authors.initials: ZF
authors.lastname: Zhang
authors.forename: Qun
authors.initials: Q
authors.lastname: Shan
authors.forename: Bin
authors.initials: B
authors.lastname: Hu
authors.forename: Meng-qiu
authors.initials: MQ
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Cheng
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D051049:Sphingosine N-Acyltransferase / Q000235:genetics* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins; C438311:CERS2 protein, human; D051049:Sphingosine N-Acyltransferase; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D025262:Vacuolar Proton-Translocating ATPases
keywords: BREAST CANCER; CERS2; INVASION; V-ATPASE