Glutaminolysis‐related genes determine sensitivity to xCT‐targeted therapy in head and neck squamous cell carcinoma

Abstract

Targeting the function of membrane transporters in cancer stemlike cells is a potential new therapeutic approach. Cystine‐glutamate antiporter xCT expressed in CD44 variant (CD44v)‐expressing cancer cells contributes to the resistance to oxidative stress as well as cancer therapy through promoting glutathione (GSH)‐mediated antioxidant defense. Amino acid transport by xCT might, thus, be a promising target for cancer treatment, whereas the determination factors for cancer cell sensitivity to xCT‐targeted therapy remain unclear. Here, we demonstrate that high expression of xCT and glutamine transporter ASCT2 is correlated with undifferentiated status and diminished along with cell differentiation in head and neck squamous cell carcinoma (HNSCC). The cytotoxicity of the xCT inhibitor sulfasalazine relies on ASCT2‐dependent glutamine uptake and glutamate dehydrogenase (GLUD)‐mediated α‐ketoglutarate (α‐KG) production. Metabolome analysis revealed that sulfasalazine treatment triggers the increase of glutamate‐derived tricarboxylic acid cycle intermediate α‐KG, in addition to the decrease of cysteine and GSH content. Furthermore, ablation of GLUD markedly reduced the sulfasalazine cytotoxicity in CD44v‐expressing stemlike HNSCC cells. Thus, xCT inhibition by sulfasalazine leads to the impairment of GSH synthesis and enhancement of mitochondrial metabolism, leading to reactive oxygen species (ROS) generation and, thereby, triggers oxidative damage. Our findings establish a rationale for the use of glutamine metabolism (glutaminolysis)‐related genes, including ASCT2 and GLUD, as biomarkers to predict the efficacy of xCT‐targeted therapy for heterogeneous HNSCC tumors.

Photodynamic therapy regulates fate of cancer stem cells through reactive oxygen species

“…Currently, little is known about the relationship between typical stemness markers and the regulation of CSC metabolism, but researchers have shown that the stem cell marker CD44 may be crucial in the regulation of glycolytic metabolism[ 142 , 143 ]. The direct interaction between CD44 and the GSH transporter--solute carrier family 7 member 11 has been reported in multiple PDT articles[ 144 , 145 ], also suggesting the ability of PDT to manipulate CSCs through redox and energy metabolism.…”

Beyond the Warburg Effect: N-Myc Contributes to Metabolic Reprogramming in Cancer Cells

“…Glutamine contributes to the synthesis of α-ketoglutarate (α-KG) via its conversion to glutamate, thereby promoting the tricarboxylic acid (TCA) cycle and the synthesis of nucleotides required for cellular proliferation (27,29). CD44 variant (CD44v)-positive cancer stem-like cells (CSCs) express high levels of xCT and ASCT2, which promote GSH synthesis from cysteine and α-KG from glutamine, respectively (30). Because c-Myc regulates amino acid transporters such as ASCT2 (23), c-Myc is likely to induce metabolic reprogramming in CD44v-positive CSCs.…”

Cysteine Depletion, a Key Action to Challenge Cancer Cells to Ferroptotic Cell Death

“…Indeed, in 1988 Bannai reported glutamine import via ASCT2 and conversion into glutamate that is exported in exchange of cystine import (1:1) via xCT (45). Yet, more recently, a metabolomic analysis reveals the importance of glutamine uptake by ASCT2 and its conversion into ROSproducing intermediate metabolite α-Ketoglutarate as marker of sensitivity during sulfasalazine xCT-inhibition cell death in head and neck squamous cells carcinoma (46). Glutaminolysis was also reported to sensitize melanoma cells to ferroptosis (47).…”