title: Lipid phosphate phosphatase-1 expression in cancer cells attenuates tumor growth and metastasis in mice.
abstract: Lipid phosphate phosphatase-1 (LPP1) degrades lysophosphatidate (LPA) and attenuates receptor-mediated signaling. LPP1 expression is low in many cancer cells and tumors compared with normal tissues. It was hypothesized from studies with cultured cells that increasing LPP1 activity would decrease tumor growth and metastasis. This hypothesis has never been tested in vivo. To do this, we inducibly expressed LPP1 or a catalytically inactive mutant in cancer cells. Expressing active LPP1 increased extracellular LPA degradation by 5-fold. It also decreased the stimulation of Ca(2+) transients by LPA, a nondephosphorylatable LPA1/2 receptor agonist and a protease-activated receptor-1 peptide. The latter results demonstrate that LPP1 has effects downstream of receptor activation. Decreased Ca(2+) mobilization and Rho activation contributed to the effects of LPP1 in attenuating the LPA-induced migration of MDA-MB-231 breast cancer cells and their growth in 3D culture. Increasing LPP1 expression in breast and thyroid cancer cells decreased tumor growth and the metastasis by up to 80% compared with expression of inactive LPP1 or green fluorescent protein in syngeneic and xenograft mouse models. The present work demonstrates for the first time that increasing the LPP1 activity in three lines of aggressive cancer cells decreases their abilities to produce tumors and metastases in mice.
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Tang
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
authors.forename: Matthew G K
authors.initials: MG
authors.lastname: Benesch
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
authors.forename: Jay
authors.initials: J
authors.lastname: Dewald
authors.affiliation: Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta T6G 2P5, Canada.
authors.forename: Yuan Y
authors.initials: YY
authors.lastname: Zhao
authors.affiliation: Department of Chemistry, Virginia Tech, Blacksburg, VA 24061.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Patwardhan
authors.affiliation: Department of Chemistry, Virginia Tech, Blacksburg, VA 24061.
authors.forename: Webster L
authors.initials: WL
authors.lastname: Santos
authors.affiliation: Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta T6G 2P5, Canada.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Curtis
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, Alberta, T6G 2R7, Canada.
authors.forename: Todd P W
authors.initials: TP
authors.lastname: McMullen
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
authors.forename: David N
authors.initials: DN
authors.lastname: Brindley
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D010711:Phosphatidate Phosphatase / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D008246:Lysophospholipids; C112948:lipid phosphate phosphatase; D010711:Phosphatidate Phosphatase; C032881:lysophosphatidic acid
keywords: G-protein-coupled receptors; autotaxin; breast cancer; cell migration; epidermal growth factor receptor; lysophosphatidate; thyroid cancer