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Inhibition of RNA Polymerase III Augments the Anti-Cancer Properties of TNFα

SIMPLE SUMMARY: Tumour necrosis factor alpha (TNFα) is a cytokine that plays an important role in apoptosis, cell survival, as well as in inflammation and immunity. Although named for its antitumor properties, TNFα has tumour-promoting properties. TNFα is often present in large quantities in tumours...

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Autores principales: Nair, Hitha Gopalan, Jurkiewicz, Aneta, Graczyk, Damian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10000776/
https://www.ncbi.nlm.nih.gov/pubmed/36900285
http://dx.doi.org/10.3390/cancers15051495
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author Nair, Hitha Gopalan
Jurkiewicz, Aneta
Graczyk, Damian
author_facet Nair, Hitha Gopalan
Jurkiewicz, Aneta
Graczyk, Damian
author_sort Nair, Hitha Gopalan
collection PubMed
description SIMPLE SUMMARY: Tumour necrosis factor alpha (TNFα) is a cytokine that plays an important role in apoptosis, cell survival, as well as in inflammation and immunity. Although named for its antitumor properties, TNFα has tumour-promoting properties. TNFα is often present in large quantities in tumours, and cancer cells frequently acquire resistance to this cytokine. Identifying the means to sensitise the cancer cells to TNFα would have therapeutical benefits. We, therefore, sought to determine whether inhibition of RNA polymerase III (Pol III), which synthesises several essential components of the protein biosynthetic machinery, would affect the response of cancer cells to TNFα. Here we show that Pol III inhibition augments the cytotoxic and cytostatic effects of TNFα. Our data suggest that targeting Pol III may be a potential therapeutic intervention to treat colorectal cancer. ABSTRACT: Tumour necrosis factor alpha (TNFα) is a multifunctional cytokine that plays a pivotal role in apoptosis, cell survival, as well as in inflammation and immunity. Although named for its antitumor properties, TNFα also has tumour-promoting properties. TNFα is often present in large quantities in tumours, and cancer cells frequently acquire resistance to this cytokine. Consequently, TNFα may increase the proliferation and metastatic potential of cancer cells. Furthermore, the TNFα-driven increase in metastasis is a result of the ability of this cytokine to induce the epithelial-to-mesenchymal transition (EMT). Overcoming the resistance of cancer cells to TNFα may have a potential therapeutic benefit. NF-κB is a crucial transcription factor mediating inflammatory signals and has a wide-ranging role in tumour progression. NF-κB is strongly activated in response to TNFα and contributes to cell survival and proliferation. The pro-inflammatory and pro-survival function of NF-κB can be disrupted by blocking macromolecule synthesis (transcription, translation). Consistently, inhibition of transcription or translation strongly sensitises cells to TNFα-induced cell death. RNA polymerase III (Pol III) synthesises several essential components of the protein biosynthetic machinery, such as tRNA, 5S rRNA, and 7SL RNA. No studies, however, directly explored the possibility that specific inhibition of Pol III activity sensitises cancer cells to TNFα. Here we show that in colorectal cancer cells, Pol III inhibition augments the cytotoxic and cytostatic effects of TNFα. Pol III inhibition enhances TNFα-induced apoptosis and also blocks TNFα-induced EMT. Concomitantly, we observe alterations in the levels of proteins related to proliferation, migration, and EMT. Finally, our data show that Pol III inhibition is associated with lower NF-κB activation upon TNFα treatment, thus potentially suggesting the mechanism of Pol III inhibition-driven sensitisation of cancer cells to this cytokine.
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spelling pubmed-100007762023-03-11 Inhibition of RNA Polymerase III Augments the Anti-Cancer Properties of TNFα Nair, Hitha Gopalan Jurkiewicz, Aneta Graczyk, Damian Cancers (Basel) Article SIMPLE SUMMARY: Tumour necrosis factor alpha (TNFα) is a cytokine that plays an important role in apoptosis, cell survival, as well as in inflammation and immunity. Although named for its antitumor properties, TNFα has tumour-promoting properties. TNFα is often present in large quantities in tumours, and cancer cells frequently acquire resistance to this cytokine. Identifying the means to sensitise the cancer cells to TNFα would have therapeutical benefits. We, therefore, sought to determine whether inhibition of RNA polymerase III (Pol III), which synthesises several essential components of the protein biosynthetic machinery, would affect the response of cancer cells to TNFα. Here we show that Pol III inhibition augments the cytotoxic and cytostatic effects of TNFα. Our data suggest that targeting Pol III may be a potential therapeutic intervention to treat colorectal cancer. ABSTRACT: Tumour necrosis factor alpha (TNFα) is a multifunctional cytokine that plays a pivotal role in apoptosis, cell survival, as well as in inflammation and immunity. Although named for its antitumor properties, TNFα also has tumour-promoting properties. TNFα is often present in large quantities in tumours, and cancer cells frequently acquire resistance to this cytokine. Consequently, TNFα may increase the proliferation and metastatic potential of cancer cells. Furthermore, the TNFα-driven increase in metastasis is a result of the ability of this cytokine to induce the epithelial-to-mesenchymal transition (EMT). Overcoming the resistance of cancer cells to TNFα may have a potential therapeutic benefit. NF-κB is a crucial transcription factor mediating inflammatory signals and has a wide-ranging role in tumour progression. NF-κB is strongly activated in response to TNFα and contributes to cell survival and proliferation. The pro-inflammatory and pro-survival function of NF-κB can be disrupted by blocking macromolecule synthesis (transcription, translation). Consistently, inhibition of transcription or translation strongly sensitises cells to TNFα-induced cell death. RNA polymerase III (Pol III) synthesises several essential components of the protein biosynthetic machinery, such as tRNA, 5S rRNA, and 7SL RNA. No studies, however, directly explored the possibility that specific inhibition of Pol III activity sensitises cancer cells to TNFα. Here we show that in colorectal cancer cells, Pol III inhibition augments the cytotoxic and cytostatic effects of TNFα. Pol III inhibition enhances TNFα-induced apoptosis and also blocks TNFα-induced EMT. Concomitantly, we observe alterations in the levels of proteins related to proliferation, migration, and EMT. Finally, our data show that Pol III inhibition is associated with lower NF-κB activation upon TNFα treatment, thus potentially suggesting the mechanism of Pol III inhibition-driven sensitisation of cancer cells to this cytokine. MDPI 2023-02-27 /pmc/articles/PMC10000776/ /pubmed/36900285 http://dx.doi.org/10.3390/cancers15051495 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Nair, Hitha Gopalan
Jurkiewicz, Aneta
Graczyk, Damian
Inhibition of RNA Polymerase III Augments the Anti-Cancer Properties of TNFα
title Inhibition of RNA Polymerase III Augments the Anti-Cancer Properties of TNFα
title_full Inhibition of RNA Polymerase III Augments the Anti-Cancer Properties of TNFα
title_fullStr Inhibition of RNA Polymerase III Augments the Anti-Cancer Properties of TNFα
title_full_unstemmed Inhibition of RNA Polymerase III Augments the Anti-Cancer Properties of TNFα
title_short Inhibition of RNA Polymerase III Augments the Anti-Cancer Properties of TNFα
title_sort inhibition of rna polymerase iii augments the anti-cancer properties of tnfα
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10000776/
https://www.ncbi.nlm.nih.gov/pubmed/36900285
http://dx.doi.org/10.3390/cancers15051495
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