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 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. Cancer Res; 76(10); 2954-63. ©2016 AACR.

• Authors: Kenji Tsuchihashi, Shogo Okazaki, Mitsuyo Ohmura, Miyuki Ishikawa, Oltea Sampetrean, Nobuyuki Onishi, Hiroaki Wakimoto, Momoko Yoshikawa, Ryo Seishima, Yoshimi Iwasaki, Takayuki Morikawa, Shinya Abe, Ayumi Takao, Misato Shimizu, Takashi Masuko, Motoo Nagane, Frank B Furnari, Tetsu Akiyama, Makoto Suematsu, Eishi Baba, Koichi Akashi, Hideyuki Saya, Osamu Nagano
• Journal: Cancer research (Cancer Res) Vol. 76 Issue 10 Pg. 2954-63 (05 15 2016) ISSN: 1538-7445 [Electronic] United States
• PMID: 26980765 (Publication Type: Journal Article)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Amino Acid Transport System y+
• Antioxidants
• Reactive Oxygen Species
• SLC7A11 protein, human
• Glutamic Acid
• Sulfasalazine
• Cystine
• EGFR protein, human
• ErbB Receptors

Topics

• Amino Acid Transport System y+ (metabolism)
• Animals
• Antioxidants (metabolism)
• Apoptosis
• Brain Neoplasms (drug therapy, metabolism, pathology)
• Cell Membrane (metabolism)
• Cell Movement
• Cell Proliferation
• Cystine (metabolism)
• ErbB Receptors (metabolism)
• Gene Expression Regulation, Neoplastic
• Glioma (drug therapy, metabolism, pathology)
• Glutamic Acid (metabolism)
• Humans
• Mice
• Mice, Inbred NOD
• Mice, Nude
• Mice, SCID
• Reactive Oxygen Species (metabolism)
• Sulfasalazine (pharmacology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays