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

Cancer Sci. 2019 Nov;110(11):3453-3463. doi: 10.1111/cas.14182. Epub 2019 Sep 13.


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.

Keywords: ASCT2; CD44 variant; glutamate dehydrogenase; head and neck cancer; xCT.

MeSH terms

  • Amino Acid Transport System ASC / genetics
  • Amino Acid Transport System y+ / antagonists & inhibitors
  • Amino Acid Transport System y+ / metabolism*
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Antineoplastic Agents / pharmacology
  • Cell Adhesion
  • Cell Differentiation
  • Cell Line, Tumor
  • Cisplatin / pharmacology
  • Glutamate Dehydrogenase / metabolism
  • Glutamine / metabolism
  • Glutathione / metabolism*
  • Head and Neck Neoplasms / drug therapy
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / metabolism*
  • Head and Neck Neoplasms / pathology
  • Humans
  • Hyaluronan Receptors / analysis
  • Hyaluronan Receptors / metabolism
  • Ketoglutaric Acids / metabolism
  • Metabolome
  • Mice
  • Mice, Nude
  • Minor Histocompatibility Antigens / genetics
  • Mitochondria / metabolism
  • Molecular Targeted Therapy / methods*
  • Neoplastic Stem Cells / metabolism*
  • Oxidation-Reduction
  • Oxidative Stress
  • RNA, Messenger / metabolism
  • Squamous Cell Carcinoma of Head and Neck / drug therapy
  • Squamous Cell Carcinoma of Head and Neck / genetics
  • Squamous Cell Carcinoma of Head and Neck / metabolism*
  • Squamous Cell Carcinoma of Head and Neck / pathology
  • Sulfasalazine / pharmacology


  • Amino Acid Transport System ASC
  • Amino Acid Transport System y+
  • Anti-Inflammatory Agents, Non-Steroidal
  • Antineoplastic Agents
  • CD44 protein, human
  • Hyaluronan Receptors
  • Ketoglutaric Acids
  • Minor Histocompatibility Antigens
  • RNA, Messenger
  • SLC1A5 protein, human
  • SLC7A11 protein, human
  • Glutamine
  • Sulfasalazine
  • Glutamate Dehydrogenase
  • Glutathione
  • Cisplatin