The CD98 Heavy Chain Is a Marker and Regulator of Head and Neck Squamous Cell Carcinoma Radiosensitivity

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 (TCD 50 ) 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.

UniCAR T cell immunotherapy enables efficient elimination of radioresistant cancer cells

“…Median fluorescence intensity (MFI) values of stained Cal33 RR and FaDu RR were higher in comparison to the parental radiosensitive cell lines Cal33 and FaDu. This is in line with recently published data of Digomann and colleagues 33 also showing increased CD98 protein expression levels for these radioresistant cells. CD98 antigen density of all investigated tumor cell lines is above 10 6 molecules/cell (Figure 2b).…”

“…30 Both EGFR and CD98 were found to be overexpressed in HNSCC, 29,30 while high expression levels were shown to correlate with a poor prognosis. [33][34][35][36][37] Furthermore, CD98 was identified as a marker and regulator of cancer stem cells in HNSCC. 38 Ionizing radiation can boost EGFR as well as CD98hc expression.…”

“…This is in line with the fact that their downstream signaling pathways contribute to an increased level of radioresistance in tumor cells. 3,33,39,40 In this study, novel murine and humanized TMs directed against CD98hc were developed. Together with established EGFR TM, they were used to test the capability of UniCAR T cells to mediate anti-tumor responses against radioresistant HNSCC cells both in vitro and in vivo.…”

mTOR-Mediated Antioxidant Activation in Solid Tumor Radioresistance

“…xCT was related to radioresistance in human breast cancer and mouse melanoma cell lines [93,94]. CD98 contributed to radioresistance in head and neck squamous cell carcinoma [95]. CD44v induced radioresistance in human pancreatic cancer cells via increasing xCT stability [96].…”

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

“…Leucine, an essential amino acid, is acquired by the cell through counter-transport with Gln [21]. The expression of the heterodimeric glutamine antiporter Slc7A5/Slc3A2 (LAT/CD98) is associated with elevated mTORC1 activity in cancer [129]. mTORC2 is also emerging to play a crucial role in glutamine metabolism.…”