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Heterogeneity of glutamine metabolism in acquired-EGFR-TKI-resistant lung cancer.
Kim, Suntae; Jeon, Jang Su; Choi, Yong June; Baek, Ga Hee; Kim, Sang Kyum; Kang, Keon Wook.
Afiliación
  • Kim S; College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
  • Jeon JS; College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea.
  • Choi YJ; College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
  • Baek GH; College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea.
  • Kim SK; College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea.
  • Kang KW; College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: kwkang@snu.ac.kr.
Life Sci ; 291: 120274, 2022 Feb 15.
Article en En | MEDLINE | ID: mdl-34990648
AIMS: The purpose of this study was to evaluate the heterogeneities of glutamine metabolism in EGFR-TKI-resistant lung cancer cells and its potential as a therapeutic target. MAIN METHODS: Cell proliferation and cell cycle assays was performed by IncuCyte real-time analysis and flow cytometry, respectively. Tumor growth was assessed in xenografts implanted with HCC827 GR. An isotopologue analysis was conducted by LC-MS/MS using 13C-(U)-glutamine labeling to determine the amounts of metabolites. Cellular ATP and mitochondrial oxidative phosphorylation were determined by XFp analysis. KEY FINDINGS: We found that the cell growth of the two acquired EGFR-TKI-resistant lung cancer cells lines (HCC827 GR and H292 ER) depends on glutamine. In HCC827 GR, glutamine deficiency caused reduced GSH synthesis and, subsequently, enhanced ROS generation relative to their parental cells, HCC827. On the other hand, in H292 ER, glutamine mainly acted as a carbon source for TCA-cycle intermediates, and its depletion led to reduced mitochondrial ATP production. CB-839, a specific GLS inhibitor, inhibited the latter's conversion of glutamine to glutamate and exerted enhanced anti-proliferating effects on the two acquired EGFR-TKI-resistant lung cancer cell lines versus their parental cell lines. Moreover, oral administration of CB-839 significantly suppressed HCC827 GR tumor growth in the xenograft model. SIGNIFICANCE: These findings suggest that glutamine dependency in acquired EGFR-TKI-resistant lung cancer is heterogeneous and that inhibition of glutamine metabolism by CB-839 may serve as a therapeutic tool for acquired EGFR-TKI-resistant lung cancer.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tiadiazoles / Bencenoacetamidas / Glutamina / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Life Sci Año: 2022 Tipo del documento: Article Pais de publicación: Países Bajos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tiadiazoles / Bencenoacetamidas / Glutamina / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Life Sci Año: 2022 Tipo del documento: Article Pais de publicación: Países Bajos