Glutaminolysis-related genes determine sensitivity to xCT-targeted therapy in head and neck squamous cell carcinoma.
Amino Acid Transport System ASC
/ genetics
Amino Acid Transport System y+
/ antagonists & inhibitors
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
Humans
Hyaluronan Receptors
/ analysis
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
Sulfasalazine
/ pharmacology
ASCT2
CD44 variant
glutamate dehydrogenase
head and neck cancer
xCT
Journal
Cancer science
ISSN: 1349-7006
Titre abrégé: Cancer Sci
Pays: England
ID NLM: 101168776
Informations de publication
Date de publication:
Nov 2019
Nov 2019
Historique:
received:
14
05
2019
revised:
20
08
2019
accepted:
22
08
2019
pubmed:
25
8
2019
medline:
13
11
2019
entrez:
25
8
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31444923
doi: 10.1111/cas.14182
pmc: PMC6825010
doi:
Substances chimiques
Amino Acid Transport System ASC
0
Amino Acid Transport System y+
0
Anti-Inflammatory Agents, Non-Steroidal
0
Antineoplastic Agents
0
CD44 protein, human
0
Hyaluronan Receptors
0
Ketoglutaric Acids
0
Minor Histocompatibility Antigens
0
RNA, Messenger
0
SLC1A5 protein, human
0
SLC7A11 protein, human
0
Glutamine
0RH81L854J
Sulfasalazine
3XC8GUZ6CB
Glutamate Dehydrogenase
EC 1.4.1.2
Glutathione
GAN16C9B8O
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
3453-3463Subventions
Organisme : Japan Agency for Medical Research and Development
ID : P-CREATE/JP18cm0106512
Informations de copyright
© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
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