title: The effect of a novel frizzled 8-related antiproliferative factor on in vitro carcinoma and melanoma cell proliferation and invasion.
abstract: Antiproliferative factor (APF) is a potent frizzled protein 8-related sialoglycopeptide inhibitor of bladder epithelial cell proliferation that mediates its activity by binding to cytoskeletal associated protein 4 in the cell membrane. Synthetic asialylated APF (as-APF) (Galβ1-3GalNAcα-O-TVPAAVVVA) was previously shown to inhibit both normal bladder epithelial as well as T24 bladder carcinoma cell proliferation and heparin-binding epidermal growth factor-like growth factor (HB-EGF) production at low nanomolar concentrations, and an L: -pipecolic acid derivative (Galβ1-3GalNAcα-O-TV-pipecolic acid-AAVVVA) was also shown to inhibit normal bladder epithelial cell proliferation. To better determine their spectrum of activity, we measured the effects of these APF derivatives on the proliferation of cells derived from additional urologic carcinomas (bladder and kidney), non-urologic carcinomas (ovary, lung, colon, pancreas, and breast), and melanomas using a (3)H-thymidine incorporation assay. We also measured the effects of as-APF on cell HB-EGF and matrix metalloproteinase (MMP2) secretion plus cell invasion, using qRT-PCR, Western blot and an in vitro invasion assay. L: -pipecolic acid as-APF and/or as-APF significantly inhibited proliferation of each cell line in a dose-dependent manner with IC(50)'s in the nanomolar range, regardless of tissue origin, cell type (carcinoma vs. melanoma), or p53 or ras mutation status. as-APF also inhibited HB-EGF and MMP2 production plus in vitro invasion of tested bladder, kidney, breast, lung, and melanoma tumor cell lines, in a dose-dependent manner (IC(50) = 1-100 nM). Synthetic APF derivatives are potent inhibitors of urologic and non-urologic carcinoma plus melanoma cell proliferation, MMP2 production, and invasion, and may be useful for development as adjunctive antitumor therapy(ies).
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA. krkoch@hotmail.com
authors.forename: Kristopher R
authors.initials: KR
authors.lastname: Koch
authors.forename: Chen-Ou
authors.initials: CO
authors.lastname: Zhang
authors.forename: Piotr
authors.initials: P
authors.lastname: Kaczmarek
authors.forename: Joseph
authors.initials: J
authors.lastname: Barchi
authors.forename: Li
authors.initials: L
authors.lastname: Guo
authors.forename: Hanief M
authors.initials: HM
authors.lastname: Shahjee
authors.forename: Susan
authors.initials: S
authors.lastname: Keay
mesh_terms: D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D006023:Glycoproteins / Q000494:pharmacology*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D011379:Prognosis; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000378:metabolism; D001743:Urinary Bladder / Q000378:metabolism / Q000473:pathology
chemical_list: C529739:Fzd8 protein, human; D006023:Glycoproteins; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D011956:Receptors, Cell Surface; D012795:Sialoglycoproteins; C490708:antiproliferative factor APF, human; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2