Activation of LXRβ inhibits tumor respiration and is synthetically lethal with Bcl‐xL inhibition
Abstract Liver‐X‐receptor (LXR) agonists are known to bear anti‐tumor activity. However, their efficacy is limited and additional insights regarding the underlying mechanism are necessary. By performing transcriptome analysis coupled with global polar metabolite screening, we show that LXR agonists,...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2019-10-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201910769 |
| _version_ | 1797285176301060096 |
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| author | Trang Thi Thu Nguyen Chiaki Tsuge Ishida Enyuan Shang Chang Shu Consuelo Torrini Yiru Zhang Elena Bianchetti Maria J Sanchez‐Quintero Giulio Kleiner Catarina M Quinzii Mike‐Andrew Westhoff Georg Karpel‐Massler Peter Canoll Markus D Siegelin |
| author_facet | Trang Thi Thu Nguyen Chiaki Tsuge Ishida Enyuan Shang Chang Shu Consuelo Torrini Yiru Zhang Elena Bianchetti Maria J Sanchez‐Quintero Giulio Kleiner Catarina M Quinzii Mike‐Andrew Westhoff Georg Karpel‐Massler Peter Canoll Markus D Siegelin |
| author_sort | Trang Thi Thu Nguyen |
| collection | DOAJ |
| description | Abstract Liver‐X‐receptor (LXR) agonists are known to bear anti‐tumor activity. However, their efficacy is limited and additional insights regarding the underlying mechanism are necessary. By performing transcriptome analysis coupled with global polar metabolite screening, we show that LXR agonists, LXR623 and GW3965, enhance synergistically the anti‐proliferative effect of BH3 mimetics in solid tumor malignancies, which is predominantly mediated by cell death with features of apoptosis and is rescued by exogenous cholesterol. Extracellular flux analysis and carbon tracing experiments (U‐13C‐glucose and U‐13C‐glutamine) reveal that within 5 h, activation of LXRβ results in reprogramming of tumor cell metabolism, leading to suppression of mitochondrial respiration, a phenomenon not observed in normal human astrocytes. LXR activation elicits a suppression of respiratory complexes at the protein level by reducing their stability. In turn, energy starvation drives an integrated stress response (ISR) that up‐regulates pro‐apoptotic Noxa in an ATF4‐dependent manner. Cholesterol and nucleotides rescue from the ISR elicited by LXR agonists and from cell death induced by LXR agonists and BH3 mimetics. In conventional and patient‐derived xenograft models of colon carcinoma, melanoma, and glioblastoma, the combination treatment of ABT263 and LXR agonists reduces tumor sizes significantly stronger than single treatments. Therefore, the combination treatment of LXR agonists and BH3 mimetics might be a viable efficacious treatment approach for solid malignancies. |
| first_indexed | 2024-03-07T17:58:28Z |
| format | Article |
| id | doaj.art-34407949ed7c4e12861f0104f22e7368 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:58:28Z |
| publishDate | 2019-10-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-34407949ed7c4e12861f0104f22e73682024-03-02T11:14:04ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842019-10-011110n/an/a10.15252/emmm.201910769Activation of LXRβ inhibits tumor respiration and is synthetically lethal with Bcl‐xL inhibitionTrang Thi Thu Nguyen0Chiaki Tsuge Ishida1Enyuan Shang2Chang Shu3Consuelo Torrini4Yiru Zhang5Elena Bianchetti6Maria J Sanchez‐Quintero7Giulio Kleiner8Catarina M Quinzii9Mike‐Andrew Westhoff10Georg Karpel‐Massler11Peter Canoll12Markus D Siegelin13Department of Pathology & Cell Biology Columbia University Medical Center New York NY USADepartment of Pathology & Cell Biology Columbia University Medical Center New York NY USADepartment of Biological Sciences Bronx Community College City University of New York Bronx NY USADepartment of Pathology & Cell Biology Columbia University Medical Center New York NY USADepartment of Pathology & Cell Biology Columbia University Medical Center New York NY USADepartment of Pathology & Cell Biology Columbia University Medical Center New York NY USADepartment of Pathology & Cell Biology Columbia University Medical Center New York NY USADepartment of Neurology Columbia University Medical Center New York NY USADepartment of Neurology Columbia University Medical Center New York NY USADepartment of Neurology Columbia University Medical Center New York NY USADepartment of Pediatrics and Adolescent Medicine Ulm University Medical Center Ulm GermanyDepartment of Neurosurgery Ulm University Medical Center Ulm GermanyDepartment of Pathology & Cell Biology Columbia University Medical Center New York NY USADepartment of Pathology & Cell Biology Columbia University Medical Center New York NY USAAbstract Liver‐X‐receptor (LXR) agonists are known to bear anti‐tumor activity. However, their efficacy is limited and additional insights regarding the underlying mechanism are necessary. By performing transcriptome analysis coupled with global polar metabolite screening, we show that LXR agonists, LXR623 and GW3965, enhance synergistically the anti‐proliferative effect of BH3 mimetics in solid tumor malignancies, which is predominantly mediated by cell death with features of apoptosis and is rescued by exogenous cholesterol. Extracellular flux analysis and carbon tracing experiments (U‐13C‐glucose and U‐13C‐glutamine) reveal that within 5 h, activation of LXRβ results in reprogramming of tumor cell metabolism, leading to suppression of mitochondrial respiration, a phenomenon not observed in normal human astrocytes. LXR activation elicits a suppression of respiratory complexes at the protein level by reducing their stability. In turn, energy starvation drives an integrated stress response (ISR) that up‐regulates pro‐apoptotic Noxa in an ATF4‐dependent manner. Cholesterol and nucleotides rescue from the ISR elicited by LXR agonists and from cell death induced by LXR agonists and BH3 mimetics. In conventional and patient‐derived xenograft models of colon carcinoma, melanoma, and glioblastoma, the combination treatment of ABT263 and LXR agonists reduces tumor sizes significantly stronger than single treatments. Therefore, the combination treatment of LXR agonists and BH3 mimetics might be a viable efficacious treatment approach for solid malignancies.https://doi.org/10.15252/emmm.201910769BH3 mimeticscolon adenocarcinomaelectron transport chainglioblastomaLXR agonist |
| spellingShingle | Trang Thi Thu Nguyen Chiaki Tsuge Ishida Enyuan Shang Chang Shu Consuelo Torrini Yiru Zhang Elena Bianchetti Maria J Sanchez‐Quintero Giulio Kleiner Catarina M Quinzii Mike‐Andrew Westhoff Georg Karpel‐Massler Peter Canoll Markus D Siegelin Activation of LXRβ inhibits tumor respiration and is synthetically lethal with Bcl‐xL inhibition EMBO Molecular Medicine BH3 mimetics colon adenocarcinoma electron transport chain glioblastoma LXR agonist |
| title | Activation of LXRβ inhibits tumor respiration and is synthetically lethal with Bcl‐xL inhibition |
| title_full | Activation of LXRβ inhibits tumor respiration and is synthetically lethal with Bcl‐xL inhibition |
| title_fullStr | Activation of LXRβ inhibits tumor respiration and is synthetically lethal with Bcl‐xL inhibition |
| title_full_unstemmed | Activation of LXRβ inhibits tumor respiration and is synthetically lethal with Bcl‐xL inhibition |
| title_short | Activation of LXRβ inhibits tumor respiration and is synthetically lethal with Bcl‐xL inhibition |
| title_sort | activation of lxrβ inhibits tumor respiration and is synthetically lethal with bcl xl inhibition |
| topic | BH3 mimetics colon adenocarcinoma electron transport chain glioblastoma LXR agonist |
| url | https://doi.org/10.15252/emmm.201910769 |
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