title: Secreted protein acidic and rich in cysteine (SPARC) induces lipotoxicity in neuroblastoma by regulating transport of albumin complexed with fatty acids.
abstract: SPARC is a matrix protein that mediates interactions between cells and the microenvironment. In cancer, SPARC may either promote or inhibit tumor growth depending upon the tumor type. In neuroblastoma, SPARC is expressed in the stromal Schwannian cells and functions as a tumor suppressor. Here, we developed a novel in vivo model of stroma-rich neuroblastoma using non-tumorigenic SHEP cells with modulated levels of SPARC, mixed with tumorigenic KCNR cells. Tumors with stroma-derived SPARC displayed suppressed growth, inhibited angiogenesis and increased lipid accumulation. Based on the described chaperone function of SPARC, we hypothesized that SPARC binds albumin complexed with fatty acids and transports them to tumors. We show that SPARC binds albumin with Kd=18.9±2.3 uM, and enhances endothelial cell internalization and transendothelial transport of albumin in vitro. We also demonstrate that lipids induce toxicity in neuroblastoma cells and show that lipotoxicity is increased when cells are cultured in hypoxic conditions. Studies investigating the therapeutic potential of SPARC are warranted.
authors: Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors: Alexandre
authors: A
authors: Chlenski
authors: Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors: Marija
authors: M
authors: Dobratic
authors: Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors: Helen R
authors: HR
authors: Salwen
authors: Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors: Mark
authors: M
authors: Applebaum
authors: Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors: Lisa J
authors: LJ
authors: Guerrero
authors: Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors: Ryan
authors: R
authors: Miller
authors: Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors: Gillian
authors: G
authors: DeWane
authors: Biological Sciences Division, Biophysics Core Facility, University of Chicago, Chicago, IL, USA.
authors: Elena
authors: E
authors: Solomaha
authors: Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors: Jeremy D
authors: JD
authors: Marks
authors: Department of Pediatrics, University of Chicago, Chicago, IL, USA.
authors: Susan L
authors: SL
authors: Cohn
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D015316:Genetic Therapy; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D051379:Mice; D008954:Models, Biological; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D015676:Osteonectin / Q000235:genetics* / Q000378:metabolism*; D019308:Palmitic Acid / Q000737:chemistry / Q000494:pharmacology*; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000378:metabolism*
chemical_list: D015676:Osteonectin; C577241:SPARC protein, human; D012710:Serum Albumin, Bovine; D019308:Palmitic Acid
keywords: SPARC; albumin; extracellular matrix; lipotoxicity; neuroblastoma