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BH3-only protein expression determines hepatocellular carcinoma response to sorafenib-based treatment
Hepatocellular carcinoma (HCC) represents a global health challenge with limited therapeutic options. Anti-angiogenic immune checkpoint inhibitor-based combination therapy has been introduced for progressed HCC, but improves survival only in a subset of HCC patients. Tyrosine-kinase inhibitors (TKI)...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313681/ https://www.ncbi.nlm.nih.gov/pubmed/34312366 http://dx.doi.org/10.1038/s41419-021-04020-z |
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author | Busche, Stephanie John, Katharina Wandrer, Franziska Vondran, Florian W. R. Lehmann, Ulrich Wedemeyer, Heiner Essmann, Frank Schulze-Osthoff, Klaus Bantel, Heike |
author_facet | Busche, Stephanie John, Katharina Wandrer, Franziska Vondran, Florian W. R. Lehmann, Ulrich Wedemeyer, Heiner Essmann, Frank Schulze-Osthoff, Klaus Bantel, Heike |
author_sort | Busche, Stephanie |
collection | PubMed |
description | Hepatocellular carcinoma (HCC) represents a global health challenge with limited therapeutic options. Anti-angiogenic immune checkpoint inhibitor-based combination therapy has been introduced for progressed HCC, but improves survival only in a subset of HCC patients. Tyrosine-kinase inhibitors (TKI) such as sorafenib represent an alternative treatment option but have only modest efficacy. Using different HCC cell lines and HCC tissues from various patients reflecting HCC heterogeneity, we investigated whether the sorafenib response could be enhanced by combination with pro-apoptotic agents, such as TNF-related apoptosis-inducing ligand (TRAIL) or the BH3-mimetic ABT-737, which target the death receptor and mitochondrial pathway of apoptosis, respectively. We found that both agents could enhance sorafenib-induced cell death which was, however, dependent on specific BH3-only proteins. TRAIL augmented sorafenib-induced cell death only in NOXA-expressing HCC cells, whereas ABT-737 enhanced the sorafenib response also in NOXA-deficient cells. ABT-737, however, failed to augment sorafenib cytotoxicity in the absence of BIM, even when NOXA was strongly expressed. In the presence of NOXA, BIM-deficient HCC cells could be in turn strongly sensitized for cell death induction by the combination of sorafenib with TRAIL. Accordingly, HCC tissues sensitive to apoptosis induction by sorafenib and TRAIL revealed enhanced NOXA expression compared to HCC tissues resistant to this treatment combination. Thus, our results suggest that BH3-only protein expression determines the treatment response of HCC to different sorafenib-based drug combinations. Individual profiling of BH3-only protein expression might therefore assist patient stratification to certain TKI-based HCC therapies. |
format | Online Article Text |
id | pubmed-8313681 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-83136812021-08-02 BH3-only protein expression determines hepatocellular carcinoma response to sorafenib-based treatment Busche, Stephanie John, Katharina Wandrer, Franziska Vondran, Florian W. R. Lehmann, Ulrich Wedemeyer, Heiner Essmann, Frank Schulze-Osthoff, Klaus Bantel, Heike Cell Death Dis Article Hepatocellular carcinoma (HCC) represents a global health challenge with limited therapeutic options. Anti-angiogenic immune checkpoint inhibitor-based combination therapy has been introduced for progressed HCC, but improves survival only in a subset of HCC patients. Tyrosine-kinase inhibitors (TKI) such as sorafenib represent an alternative treatment option but have only modest efficacy. Using different HCC cell lines and HCC tissues from various patients reflecting HCC heterogeneity, we investigated whether the sorafenib response could be enhanced by combination with pro-apoptotic agents, such as TNF-related apoptosis-inducing ligand (TRAIL) or the BH3-mimetic ABT-737, which target the death receptor and mitochondrial pathway of apoptosis, respectively. We found that both agents could enhance sorafenib-induced cell death which was, however, dependent on specific BH3-only proteins. TRAIL augmented sorafenib-induced cell death only in NOXA-expressing HCC cells, whereas ABT-737 enhanced the sorafenib response also in NOXA-deficient cells. ABT-737, however, failed to augment sorafenib cytotoxicity in the absence of BIM, even when NOXA was strongly expressed. In the presence of NOXA, BIM-deficient HCC cells could be in turn strongly sensitized for cell death induction by the combination of sorafenib with TRAIL. Accordingly, HCC tissues sensitive to apoptosis induction by sorafenib and TRAIL revealed enhanced NOXA expression compared to HCC tissues resistant to this treatment combination. Thus, our results suggest that BH3-only protein expression determines the treatment response of HCC to different sorafenib-based drug combinations. Individual profiling of BH3-only protein expression might therefore assist patient stratification to certain TKI-based HCC therapies. Nature Publishing Group UK 2021-07-26 /pmc/articles/PMC8313681/ /pubmed/34312366 http://dx.doi.org/10.1038/s41419-021-04020-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Busche, Stephanie John, Katharina Wandrer, Franziska Vondran, Florian W. R. Lehmann, Ulrich Wedemeyer, Heiner Essmann, Frank Schulze-Osthoff, Klaus Bantel, Heike BH3-only protein expression determines hepatocellular carcinoma response to sorafenib-based treatment |
title | BH3-only protein expression determines hepatocellular carcinoma response to sorafenib-based treatment |
title_full | BH3-only protein expression determines hepatocellular carcinoma response to sorafenib-based treatment |
title_fullStr | BH3-only protein expression determines hepatocellular carcinoma response to sorafenib-based treatment |
title_full_unstemmed | BH3-only protein expression determines hepatocellular carcinoma response to sorafenib-based treatment |
title_short | BH3-only protein expression determines hepatocellular carcinoma response to sorafenib-based treatment |
title_sort | bh3-only protein expression determines hepatocellular carcinoma response to sorafenib-based treatment |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313681/ https://www.ncbi.nlm.nih.gov/pubmed/34312366 http://dx.doi.org/10.1038/s41419-021-04020-z |
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