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

Autor: Hideyuki Saya, Daisuke Aoki, Hideki Nakayama, Yuji Otsuki, Momoko Yoshikawa, Sho Kawaguchi, Takashi Masuko, Shogo Okazaki, Kentaro Suina, Kouji Banno, Osamu Nagano, Kiyoko Umene, Yushi Minami, Juntaro Yamasaki
Rok vydání: 2019
Předmět:
0301 basic medicine
Cancer Research
medicine.medical_treatment
Glutamine
Targeted therapy
chemistry.chemical_compound
Mice
0302 clinical medicine
Glutamate Dehydrogenase
Cell
Molecular
and Stem Cell Biology
Molecular Targeted Therapy
biology
Chemistry
Anti-Inflammatory Agents
Non-Steroidal
Cell Differentiation
General Medicine
CD44 variant
Glutathione
ASCT2
Mitochondria
Hyaluronan Receptors
Oncology
Head and Neck Neoplasms
030220 oncology & carcinogenesis
Metabolome
Neoplastic Stem Cells
Ketoglutaric Acids
Original Article
Oxidation-Reduction
Amino Acid Transport System ASC
Amino Acid Transport System y+
Mice
Nude
Antineoplastic Agents
Minor Histocompatibility Antigens
03 medical and health sciences
Cell Line
Tumor
medicine
Cell Adhesion
Animals
Humans
RNA
Messenger
Glutaminolysis
Squamous Cell Carcinoma of Head and Neck
xCT
CD44
Cancer
Original Articles
medicine.disease
Head and neck squamous-cell carcinoma
Sulfasalazine
Oxidative Stress
030104 developmental biology
Cancer cell
biology.protein
Cancer research
head and neck cancer
Cisplatin
Zdroj: Cancer Science
ISSN: 1349-7006
Popis: 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.
Databáze: OpenAIRE
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