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Activation of LXR Receptors and Inhibition of TRAP1 Causes Synthetic Lethality in Solid Tumors

Cholesterol is a pivotal factor for cancer cells to entertain their relentless growth. In this case, we provide a novel strategy to inhibit tumor growth by simultaneous activation of liver-X-receptors and interference with Tumor Necrosis Factor Receptor-associated Protein 1 (TRAP1). Informed by a tr...

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Autores principales: Nguyen, Trang Thi Thu, Ishida, Chiaki Tsuge, Shang, Enyuan, Shu, Chang, Bianchetti, Elena, Karpel-Massler, Georg, Siegelin, Markus D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627953/
https://www.ncbi.nlm.nih.gov/pubmed/31181660
http://dx.doi.org/10.3390/cancers11060788
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author Nguyen, Trang Thi Thu
Ishida, Chiaki Tsuge
Shang, Enyuan
Shu, Chang
Bianchetti, Elena
Karpel-Massler, Georg
Siegelin, Markus D.
author_facet Nguyen, Trang Thi Thu
Ishida, Chiaki Tsuge
Shang, Enyuan
Shu, Chang
Bianchetti, Elena
Karpel-Massler, Georg
Siegelin, Markus D.
author_sort Nguyen, Trang Thi Thu
collection PubMed
description Cholesterol is a pivotal factor for cancer cells to entertain their relentless growth. In this case, we provide a novel strategy to inhibit tumor growth by simultaneous activation of liver-X-receptors and interference with Tumor Necrosis Factor Receptor-associated Protein 1 (TRAP1). Informed by a transcriptomic and subsequent gene set enrichment analysis, we demonstrate that inhibition of TRAP1 results in suppression of the cholesterol synthesis pathway in stem-like and established glioblastoma (GBM) cells by destabilizing the transcription factor SREBP2. Notably, TRAP1 inhibition induced cell death, which was rescued by cholesterol and mevalonate. Activation of liver X receptor (LXR) by a clinically validated LXR agonist, LXR623, along with the TRAP1 inhibitor, gamitrinib (GTPP), results in synergistic reduction of tumor growth and cell death induction in a broad range of solid tumors, which is rescued by exogenous cholesterol. The LXR agonist and TRAP1 inhibitor mediated cell death is regulated at the level of Bcl-2 family proteins with an elevation of pro-apoptotic Noxa. Silencing of Noxa and its effector BAK attenuates cell death mediated by the combination treatment of LXR agonists and TRAP1 inhibition. Combined inhibition of TRAP1 and LXR agonists elicits a synergistic activation of the integrated stress response with an increase in activating transcription factor 4 (ATF4) driven by protein kinase RNA-like endoplasmic reticulum kinase (PERK). Silencing of ATF4 attenuates the increase of Noxa by using the combination treatment. Lastly, we demonstrate in patient-derived xenografts that the combination treatment of LXR623 and gamitrinib reduces tumor growth more potent than each compound. Taken together, these results suggest that TRAP1 inhibition and simultaneous activation of LXR might be a potent novel treatment strategy for solid malignancies.
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spelling pubmed-66279532019-07-23 Activation of LXR Receptors and Inhibition of TRAP1 Causes Synthetic Lethality in Solid Tumors Nguyen, Trang Thi Thu Ishida, Chiaki Tsuge Shang, Enyuan Shu, Chang Bianchetti, Elena Karpel-Massler, Georg Siegelin, Markus D. Cancers (Basel) Article Cholesterol is a pivotal factor for cancer cells to entertain their relentless growth. In this case, we provide a novel strategy to inhibit tumor growth by simultaneous activation of liver-X-receptors and interference with Tumor Necrosis Factor Receptor-associated Protein 1 (TRAP1). Informed by a transcriptomic and subsequent gene set enrichment analysis, we demonstrate that inhibition of TRAP1 results in suppression of the cholesterol synthesis pathway in stem-like and established glioblastoma (GBM) cells by destabilizing the transcription factor SREBP2. Notably, TRAP1 inhibition induced cell death, which was rescued by cholesterol and mevalonate. Activation of liver X receptor (LXR) by a clinically validated LXR agonist, LXR623, along with the TRAP1 inhibitor, gamitrinib (GTPP), results in synergistic reduction of tumor growth and cell death induction in a broad range of solid tumors, which is rescued by exogenous cholesterol. The LXR agonist and TRAP1 inhibitor mediated cell death is regulated at the level of Bcl-2 family proteins with an elevation of pro-apoptotic Noxa. Silencing of Noxa and its effector BAK attenuates cell death mediated by the combination treatment of LXR agonists and TRAP1 inhibition. Combined inhibition of TRAP1 and LXR agonists elicits a synergistic activation of the integrated stress response with an increase in activating transcription factor 4 (ATF4) driven by protein kinase RNA-like endoplasmic reticulum kinase (PERK). Silencing of ATF4 attenuates the increase of Noxa by using the combination treatment. Lastly, we demonstrate in patient-derived xenografts that the combination treatment of LXR623 and gamitrinib reduces tumor growth more potent than each compound. Taken together, these results suggest that TRAP1 inhibition and simultaneous activation of LXR might be a potent novel treatment strategy for solid malignancies. MDPI 2019-06-07 /pmc/articles/PMC6627953/ /pubmed/31181660 http://dx.doi.org/10.3390/cancers11060788 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Nguyen, Trang Thi Thu
Ishida, Chiaki Tsuge
Shang, Enyuan
Shu, Chang
Bianchetti, Elena
Karpel-Massler, Georg
Siegelin, Markus D.
Activation of LXR Receptors and Inhibition of TRAP1 Causes Synthetic Lethality in Solid Tumors
title Activation of LXR Receptors and Inhibition of TRAP1 Causes Synthetic Lethality in Solid Tumors
title_full Activation of LXR Receptors and Inhibition of TRAP1 Causes Synthetic Lethality in Solid Tumors
title_fullStr Activation of LXR Receptors and Inhibition of TRAP1 Causes Synthetic Lethality in Solid Tumors
title_full_unstemmed Activation of LXR Receptors and Inhibition of TRAP1 Causes Synthetic Lethality in Solid Tumors
title_short Activation of LXR Receptors and Inhibition of TRAP1 Causes Synthetic Lethality in Solid Tumors
title_sort activation of lxr receptors and inhibition of trap1 causes synthetic lethality in solid tumors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627953/
https://www.ncbi.nlm.nih.gov/pubmed/31181660
http://dx.doi.org/10.3390/cancers11060788
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