Targeting Ribosome Biogenesis in Cancer: Lessons Learned and Way Forward
Rapid growth and unrestrained proliferation is a hallmark of many cancers. To accomplish this, cancer cells re-wire and increase their biosynthetic and metabolic activities, including ribosome biogenesis (RiBi), a complex, highly energy-consuming process. Several chemotherapeutic agents used in the...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-04-01
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| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/14/9/2126 |
| _version_ | 1797505366730211328 |
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| author | Asimina Zisi Jiri Bartek Mikael S. Lindström |
| author_facet | Asimina Zisi Jiri Bartek Mikael S. Lindström |
| author_sort | Asimina Zisi |
| collection | DOAJ |
| description | Rapid growth and unrestrained proliferation is a hallmark of many cancers. To accomplish this, cancer cells re-wire and increase their biosynthetic and metabolic activities, including ribosome biogenesis (RiBi), a complex, highly energy-consuming process. Several chemotherapeutic agents used in the clinic impair this process by interfering with the transcription of ribosomal RNA (rRNA) in the nucleolus through the blockade of RNA polymerase I or by limiting the nucleotide building blocks of RNA, thereby ultimately preventing the synthesis of new ribosomes. Perturbations in RiBi activate nucleolar stress response pathways, including those controlled by p53. While compounds such as actinomycin D and oxaliplatin effectively disrupt RiBi, there is an ongoing effort to improve the specificity further and find new potent RiBi-targeting compounds with improved pharmacological characteristics. A few recently identified inhibitors have also become popular as research tools, facilitating our advances in understanding RiBi. Here we provide a comprehensive overview of the various compounds targeting RiBi, their mechanism of action, and potential use in cancer therapy. We discuss screening strategies, drug repurposing, and common problems with compound specificity and mechanisms of action. Finally, emerging paths to discovery and avenues for the development of potential biomarkers predictive of therapeutic outcomes across cancer subtypes are also presented. |
| first_indexed | 2024-03-10T04:18:35Z |
| format | Article |
| id | doaj.art-06a4e9175b43413d83503fe942fa6183 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T04:18:35Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-06a4e9175b43413d83503fe942fa61832023-11-23T07:55:15ZengMDPI AGCancers2072-66942022-04-01149212610.3390/cancers14092126Targeting Ribosome Biogenesis in Cancer: Lessons Learned and Way ForwardAsimina Zisi0Jiri Bartek1Mikael S. Lindström2Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SciLifeLab, S-171 21 Stockholm, SwedenDivision of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SciLifeLab, S-171 21 Stockholm, SwedenDivision of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SciLifeLab, S-171 21 Stockholm, SwedenRapid growth and unrestrained proliferation is a hallmark of many cancers. To accomplish this, cancer cells re-wire and increase their biosynthetic and metabolic activities, including ribosome biogenesis (RiBi), a complex, highly energy-consuming process. Several chemotherapeutic agents used in the clinic impair this process by interfering with the transcription of ribosomal RNA (rRNA) in the nucleolus through the blockade of RNA polymerase I or by limiting the nucleotide building blocks of RNA, thereby ultimately preventing the synthesis of new ribosomes. Perturbations in RiBi activate nucleolar stress response pathways, including those controlled by p53. While compounds such as actinomycin D and oxaliplatin effectively disrupt RiBi, there is an ongoing effort to improve the specificity further and find new potent RiBi-targeting compounds with improved pharmacological characteristics. A few recently identified inhibitors have also become popular as research tools, facilitating our advances in understanding RiBi. Here we provide a comprehensive overview of the various compounds targeting RiBi, their mechanism of action, and potential use in cancer therapy. We discuss screening strategies, drug repurposing, and common problems with compound specificity and mechanisms of action. Finally, emerging paths to discovery and avenues for the development of potential biomarkers predictive of therapeutic outcomes across cancer subtypes are also presented.https://www.mdpi.com/2072-6694/14/9/2126ribosome biogenesisnucleolusp53cancerRNA polymerase Itranslation |
| spellingShingle | Asimina Zisi Jiri Bartek Mikael S. Lindström Targeting Ribosome Biogenesis in Cancer: Lessons Learned and Way Forward Cancers ribosome biogenesis nucleolus p53 cancer RNA polymerase I translation |
| title | Targeting Ribosome Biogenesis in Cancer: Lessons Learned and Way Forward |
| title_full | Targeting Ribosome Biogenesis in Cancer: Lessons Learned and Way Forward |
| title_fullStr | Targeting Ribosome Biogenesis in Cancer: Lessons Learned and Way Forward |
| title_full_unstemmed | Targeting Ribosome Biogenesis in Cancer: Lessons Learned and Way Forward |
| title_short | Targeting Ribosome Biogenesis in Cancer: Lessons Learned and Way Forward |
| title_sort | targeting ribosome biogenesis in cancer lessons learned and way forward |
| topic | ribosome biogenesis nucleolus p53 cancer RNA polymerase I translation |
| url | https://www.mdpi.com/2072-6694/14/9/2126 |
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