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

Shogo Okazaki, Kiyoko Umene, Juntaro Yamasaki, Kentaro Suina, Yuji Otsuki, Momoko Yoshikawa, Yushi Minami, Takashi Masuko, Sho Kawaguchi, Hideki Nakayama, Kouji Banno, Daisuke Aoki, Hideyuki Saya, Osamu Nagano

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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.

Original languageEnglish
Pages (from-to)3453-3463
Number of pages11
JournalCancer science
Volume110
Issue number11
DOIs
Publication statusPublished - 2019 Nov 1

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Keywords

  • ASCT2
  • CD44 variant
  • glutamate dehydrogenase
  • head and neck cancer
  • xCT

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Okazaki, S., Umene, K., Yamasaki, J., Suina, K., Otsuki, Y., Yoshikawa, M., Minami, Y., Masuko, T., Kawaguchi, S., Nakayama, H., Banno, K., Aoki, D., Saya, H., & Nagano, O. (2019). Glutaminolysis-related genes determine sensitivity to xCT-targeted therapy in head and neck squamous cell carcinoma. Cancer science, 110(11), 3453-3463. https://doi.org/10.1111/cas.14182