RRC ID 59953
Author 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.
Title Glutaminolysis-related genes determine sensitivity to xCT-targeted therapy in head and neck squamous cell carcinoma.
Journal Cancer Sci
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.
Volume 110(11)
Pages 3453-3463
Published 2019-11
DOI 10.1111/cas.14182
PMID 31444923
PMC PMC6825010
MeSH 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
IF 4.751
Times Cited 6
Human and Animal Cells HSC-2(RCB1945), HSC-4(RCB1902)