# Regulation of Amino-acid Transport in Human Gliomas

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2022 · $362,043

## Abstract

Project Summary/Abstract
Glutamate (Glu) has emerged as an important molecule in the biology of malignant brain tumors, specifically
gliomas1. Glu can reach toxic concentrations in peritumoral tissue, contributing to enhanced tumor growth and
invasion, as well as peritumoral edema, excitotoxicity, and seizures2. Mediated by the cystine-glutamate
exchanger, System xc- (SXC), Glu uptake supplies cystine for production of the intracellular antioxidant
glutathione (GSH). GSH protects cells from endogenous and exogenous stressors3, including radiation and
chemotherapy. GSH over-production confers resistance to radiation4-6 and ferroptosis7, an iron-dependent form
of programmed cell death. In previous studies, we show that xCT, the catalytic subunit of SXC, is variably
expressed among glioma patients8. Approximately half of tumors show elevated xCT expression and present
with seizures and Glu excitotoxicity, whereas gliomas with low xCT expression do not. Similarly, in a clinical pilot
study, we show that pharmacological inhibition of SXC reduces Glu release only in gliomas with elevated xCT
expression8. Based on recent, data we now hypothesize that differences in the expression and function of SXC
are due to its transcriptional and co-receptor regulation. We hypothesize that xCT is transcriptionally regulated
by p53, with wild type p53 acting as transcriptional suppressor. As p53 is mutated or deleted in many gliomas,
this alteration would result in aberrant overexpression of xCT, explaining the observed Glu release and
downstream pathophysiology. We also hypothesize, based on preliminary findings, that the activity of SXC is
regulated by extracellular matrix components activating the hyaluronic acid receptor CD44, which serves as a
functional co-receptor for SXC. Both p53 and CD44 activity can alter glioma biology and determine peritumoral
excitotoxicity, seizures, invasion, and growth. The proposed studies are significant and clinically relevant as they
explore new strategies to interfere with the abnormal glutamate biology of gliomas at a transcription and
expression level. This proposal provides superior strategies to currently available pharmacological inhibitors for
SXC, which have poor specificity and bioavailability. Moreover, the expression of p53 and CD44 may have
predictive value regarding potential personalized treatments for this subgroup of glioma in the future.

## Key facts

- **NIH application ID:** 10321925
- **Project number:** 5R01CA227149-05
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** HARALD W SONTHEIMER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $362,043
- **Award type:** 5
- **Project period:** 2018-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10321925

## Citation

> US National Institutes of Health, RePORTER application 10321925, Regulation of Amino-acid Transport in Human Gliomas (5R01CA227149-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10321925. Licensed CC0.

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