The EGF Receptor Promotes the Malignant Potential of Glioma by Regulating Amino Acid Transport System xc(—)

Abstract

Extracellular free amino acids contribute to the interaction between a tumor and its microenvironment through effects on cellular metabolism and malignant behavior. System xc(−) is composed of xCT and CD98hc subunits and functions as a plasma membrane antiporter for the uptake of extracellular cystine in exchange for intracellular glutamate. Here we show that the epidermal growth factor receptor (EGFR) interacts with xCT and thereby promotes its cell surface expression and function in human glioma cells. EGFR-expressing glioma cells manifested both enhanced antioxidant capacity as a result of increased cystine uptake as well as increased glutamate which promotes matrix invasion. Imaging mass spectrometry also revealed that brain tumors formed in mice by human glioma cells stably overexpressing EGFR contained higher levels of reduced glutathione compared with those formed by parental cells. Targeted inhibition of xCT suppressed the EGFR-dependent enhancement of antioxidant capacity in glioma cells as well as tumor growth and invasiveness. Our findings establish a new functional role for EGFR in promoting the malignant potential of glioma cells through interaction with xCT at the cell surface.

mTORC2 Regulates Amino Acid Metabolism in Cancer by Phosphorylation of the Cystine-Glutamate Antiporter xCT

“…xCT-bound complexes were immunoprecipitated and subjected to quantitative LC/MS-MS (Figure 1A), revealing 125 potential xCT binding proteins with a median fold enrichment of xCT/vector > 10, Log 10 (xCT/vector) > 1 (Figure 1B and Table S1), that enriched in pathways involved in cellular and protein metabolism by DAVID (Huang da et al, 2009) Gene Ontology (GO) analysis (Figure 1C and Table S2). Established xCT binding partners including CD98 ( SLC3A2 ), part of system x C − , and CD44, an obligate binding partner (Ishimoto et al, 2011), were identified as well as the recently described binding partner epidermal growth factor receptor (EGFR) (Tsuchihashi et al, 2016). Surprisingly, Rictor and mTOR, which are core components of mTOR complex 2 (mTORC2), were also identified as potential xCT binding partners (Figure 1B).…”

Redox-Related Epigenetic Mechanisms in Glioblastoma: Nuclear Factor (Erythroid-Derived 2)-Like 2, Cobalamin, and Dopamine Receptor Subtype 4

“…Epidermal growth factor receptor activation in C6 glioma cells upregulates xCT in association with increased GSH levels (48). In mice, EGFR-overexpressing gliomas are associated with greater invasiveness, and the xCT inhibitor sulfasalazine suppressed tumor growth and invasiveness.…”

“…Because cystine transporter activity is upregulated in glioblastoma (48), selective transporter inhibitors might be useful treatment options. Indeed, several studies have reported beneficial effects of sulfasalazine, an inhibitor of systemic Xc − -mediated cystine uptake (92, 93).…”

Epidermal growth factor receptor promotes glioma progression by regulating xCT and GluN2B‐containing N‐methyl‐d‐aspartate–sensitive glutamate receptor signaling

“…Infiltration of tumor cells into brain tissue is a pathological hallmark of malignant gliomas and is enhanced by autocrine and paracrine factors, including chemokines and growth factors such as epidermal growth factor (EGF) . Extracellular glutamate released from glioma cells has also been shown to act as an autocrine factor that promotes malignant behavior in these cells …”

“…System xc(–) comprises xCT and CD98hc subunits and is a major plasma membrane antiporter responsible for the cellular uptake of cystine in exchange for intracellular glutamate . We previously showed that the intracellular domain of EGFR interacts with and thereby promotes the surface expression of xCT in glioma cells in a manner independent of receptor kinase activity, resulting in increased cystine uptake and glutamate release . The released glutamate then acts as an autocrine factor to enhance glioma progression through interaction with glutamate receptors at the cell surface …”