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

Autor: Okazaki S; Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan.; Division of Development and Aging, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan., Umene K; Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan.; Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan., Yamasaki J; Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan., Suina K; Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan., Otsuki Y; Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan., Yoshikawa M; Department of Dentistry and Oral Surgery, School of Medicine, Keio University, Tokyo, Japan., Minami Y; Cell Biology Laboratory, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Kindai University, Higashiosaka, Japan., Masuko T; Cell Biology Laboratory, Department of Pharmaceutical Sciences, Faculty of Pharmacy, Kindai University, Higashiosaka, Japan., Kawaguchi S; Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan., Nakayama H; Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan., Banno K; Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan., Aoki D; Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan., Saya H; Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan., Nagano O; Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan.
Jazyk: angličtina
Zdroj: Cancer science [Cancer Sci] 2019 Nov; Vol. 110 (11), pp. 3453-3463. Date of Electronic Publication: 2019 Sep 13.
DOI: 10.1111/cas.14182
Abstrakt: 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.
(© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)
Databáze: MEDLINE
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