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

Shogo Okazaki1,2, Kiyoko Umene1,3, Juntaro Yamasaki1

  • 1Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan.

Cancer Science
|August 25, 2019
PubMed

Insights

Targeting cystine-glutamate antiporter xCT with sulfasalazine shows promise for head and neck cancer. Its efficacy depends on ASCT2 and GLUD, impacting glutathione synthesis and oxidative stress.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metabolism

Background:

  • Cancer stem-like cells exhibit resistance to therapy via mechanisms like oxidative stress.
  • The cystine-glutamate antiporter xCT is crucial for glutathione synthesis and antioxidant defense in cancer cells.
  • Understanding factors determining sensitivity to xCT-targeted therapy is vital for effective cancer treatment.

Purpose of the Study:

  • To investigate the role of xCT and ASCT2 in head and neck squamous cell carcinoma (HNSCC) differentiation and therapy response.
  • To elucidate the mechanism of sulfasalazine cytotoxicity in HNSCC.
  • To identify biomarkers for predicting efficacy of xCT-targeted therapy.

Main Methods:

  • Analysis of xCT and ASCT2 expression in HNSCC.
  • Assessment of sulfasalazine cytotoxicity in relation to ASCT2 and GLUD.
  • Metabolome analysis to study metabolic alterations upon sulfasalazine treatment.
  • Gene ablation studies (GLUD) to confirm functional roles.

Main Results:

  • High expression of xCT and ASCT2 correlates with undifferentiated HNSCC and decreases with differentiation.
  • Sulfasalazine cytotoxicity is dependent on ASCT2-mediated glutamine uptake and GLUD-driven α-ketoglutarate production.
  • Sulfasalazine treatment reduces cysteine and GSH levels while increasing α-ketoglutarate, leading to ROS generation and oxidative damage.
  • GLUD ablation significantly reduces sulfasalazine's cytotoxicity in CD44v-expressing HNSCC cells.

Conclusions:

  • Sulfasalazine-induced xCT inhibition impairs GSH synthesis and enhances mitochondrial metabolism, causing oxidative damage.
  • ASCT2 and GLUD are critical for sulfasalazine efficacy in HNSCC.
  • Glutamine metabolism-related genes (ASCT2, GLUD) can serve as biomarkers for predicting xCT-targeted therapy response in HNSCC.
Keywords:
ASCT2CD44 variantglutamate dehydrogenasehead and neck cancerxCT

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