Work

Secreted protein acidic and rich in cysteine (SPARC) induces lipotoxicity in neuroblastoma by regulating transport of albumin complexed with fatty acids

Year: 2016

Type: article

Abstract: // Alexandre Chlenski 1 , Marija Dobratic 1 , Helen R. Salwen 1 , Mark Applebaum 1 , Lisa J. Guerrero 1 , Ryan Miller 1 , Gillian DeWane 1 , Elena Solomaha 2 , Jeremy D. Marks 1 , Susan L. Cohn 1 1 Department of Pediatrics, University of Chicago, Chicago, IL, USA 2 Biological Sciences Division, Biophysics Core Facility, University of Chicago, Chicago, IL, USA Correspondence to: Susan L. Cohn, email: [email protected] Keywords: neuroblastoma, SPARC, albumin, lipotoxicity, extracellular matrix Received: June 08, 2016 Accepted: October 11, 2016 Published: October 20, 2016 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.12773