The CD98 heavy chain is a marker and regulator of head and neck squamous cell carcinoma radiosensitivity

David Digomann, Ina Kurth, Anna Tyutyunnykova, Oleg Chen, Steffen Lock, Ielizaveta Gorodetska, Claudia Peitzsch, Ira Ida Skvortsova, Giulia Negro, Bertram Aschenbrenner, Graeme Eisenhofer, Susan Richter, Stephan Heiden, Joseph Porrmann, Barbara Klink, Christian Schwager, Adam A. Dowle, Linda Hein, Leoni A. Kunz-Schughart, Amir AbdollahiFabian Lohaus, Mechthild Krause, Michael Baumann, Annett Linge, Anna Dubrovska*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

33 Citations (Scopus)

Abstract

Purpose: The heavy chain of the CD98 protein (CD98hc) is encoded by the SLC3A2 gene. Together with the light subunit LAT1, CD98hc constitutes a heterodimeric transmembrane amino acid transporter. High SLC3A2 mRNA expression levels are associated with poor prognosis in patients with head and neck squamous cell carcinoma (HNSCC) treated with radiochemotherapy. Little is known regarding the CD98hc protein–mediated molecular mechanisms of tumor radioresistance. Experimental Design: CD98hc protein expression levels were correlated with corresponding tumor control dose 50 (TCD50) in HNSCC xenograft models. Expression levels of CD98hc and LAT1 in HNSCC cells were modulated by siRNA or CRISPR/Cas9 gene editing. HNSCC cell phenotypes were characterized by transcription profiling, plasma membrane proteomics, metabolic analysis, and signaling pathway activation. Expression levels of CD98hc and LAT1 proteins were examined by IHC analysis of tumor tissues from patients with locally advanced HNSCC treated with primary radiochemotherapy (RCTx). Primary endpoint was locoregional tumor control (LRC). Results: High expression levels of CD98hc resulted in an increase in mTOR pathway activation, amino acid metabolism, and DNA repair as well as downregulation of oxidative stress and autophagy. High expression levels of CD98hc and LAT1 proteins were significantly correlated and associated with an increase in radioresistance in HNSCC in vitro and in vivo models. High expression of both proteins identified a poor prognosis subgroup in patients with locally advanced HNSCC after RCTx. Conclusions: We found that CD98hc-associated signaling mechanisms play a central role in the regulation of HNSCC radioresistance and may be a promising target for tumor radiosensitization.

Original languageEnglish
Pages (from-to)3152-3163
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number10
DOIs
Publication statusPublished - 2019
Externally publishedYes

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