Inhibition of RNA Polymerase III Augments the Anti-Cancer Properties of TNFα
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 tumou...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/5/1495 |
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| author | Hitha Gopalan Nair Aneta Jurkiewicz Damian Graczyk |
| author_facet | Hitha Gopalan Nair Aneta Jurkiewicz Damian Graczyk |
| author_sort | Hitha Gopalan Nair |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T07:29:25Z |
| format | Article |
| id | doaj.art-1146bf34c31444c0a2c82fa519479929 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T07:29:25Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-1146bf34c31444c0a2c82fa5194799292023-11-17T07:24:52ZengMDPI AGCancers2072-66942023-02-01155149510.3390/cancers15051495Inhibition of RNA Polymerase III Augments the Anti-Cancer Properties of TNFαHitha Gopalan Nair0Aneta Jurkiewicz1Damian Graczyk2Institute of Biochemistry and Biophysics of the Polish Academy of Sciences, ul. Pawińskiego 5a, 02-106 Warsaw, PolandInstitute of Biochemistry and Biophysics of the Polish Academy of Sciences, ul. Pawińskiego 5a, 02-106 Warsaw, PolandInstitute of Biochemistry and Biophysics of the Polish Academy of Sciences, ul. Pawińskiego 5a, 02-106 Warsaw, PolandTumour 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.https://www.mdpi.com/2072-6694/15/5/1495RNA polymerase IIIcancerTNFαNF-κB |
| spellingShingle | Hitha Gopalan Nair Aneta Jurkiewicz Damian Graczyk Inhibition of RNA Polymerase III Augments the Anti-Cancer Properties of TNFα Cancers RNA polymerase III cancer TNFα NF-κB |
| 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 | RNA polymerase III cancer TNFα NF-κB |
| url | https://www.mdpi.com/2072-6694/15/5/1495 |
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