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.

Secreted protein acidic and rich in cysteine mediates active targeting of human serum albumin in U87MG xenograft mouse models

“…Previous studies have shown a correlation between SPARC and HSA at the protein expression level in cancer cells and possible implications for the therapeutic effect but did not show a direct relationship of SPARC in HSA accumulation in tumors 32. Another study showed the binding affinity between bovine serum albumin (BSA) and SPARC, and its internalization using a non-cancer cell line and suggested that HSA may have a similar affinity to SPARC 33. Therefore, it was necessary to identify HSA and SPARC interactions in cancer cells.…”

“…BSA and SPARC binding was determined using IP methods following the previously published procedure 33. For the pre-clearing step, we incubated 10 μg of HSA, 4.76 μg/mL of normal rabbit serum (X0902, Dako, Santa Clara, CA), and 20 μl of protein A/G PLUS-Agarose (sc-2003, SCB) in a test tube for 1 h at 4 °C.…”

Glucose affects cell viability, migration, angiogenesis and cellular adhesion of human retinal capillary endothelial cells via SPARC

“…SPARC is a widely expressed profibrotic protein with pleiotropic roles, which have been studied in a variety of conditions (18,19). Previous evidence has demonstrated that SPARC was associated with human obesity and diabetes (11).…”

Albumin-Modified Melanin-Silica Hybrid Nanoparticles Target Breast Cancer Cells via a SPARC-Dependent Mechanism

“…SPARC is a secreted protein that binds albumin (albumin-binding protein) and is highly expressed in many cancers. Some studies have proposed the involvement of SPARC in the uptake of albumin in tumors ( Frei, 2011 ; Liu et al, 2015 ; Chlenski et al, 2016 ; Park et al, 2019 ) and in NPs internalization via HSA in cancer cells ( Hoang et al, 2015 ). Thanks to this feature, SPARC represents a good molecular target for the active NPs delivery.…”

“…It is the most abundant plasma protein in human blood with a molecular weight of 66.5 kDa and a molecular size of ∼7.2 nm and has been already explored as a useful medical device for therapeutic and diagnostic agents delivery, due to its non-immunogenicity and nontoxicity ( He and Carter, 1992 ; Bairagi et al, 2015 ; Mehtala et al, 2015 ). Moreover, albumin interacts with cellular receptors that include glycoproteins Gp60, Gp30, and Gp18 and the secreted protein acidic and rich in cysteine (SPARC), and these interactions can be used for a specific targeted delivery of NPs ( Schnitzer, 1992 ; Tiruppathi et al, 1996 ; Desai et al, 2009 ; Chlenski et al, 2016 ). Particular interest among albumin binding proteins is attracted by SPARC, which is overexpressed in the extracellular matrix and in various cancer cells and is associated with tissue growth and cell proliferation.…”