Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53
Megan J Bywater, Gretchen Poortinga, Elaine Sanij, Nadine Hein, Abigail Peck, Carleen Cullinane, Meaghan Wall, Leonie Cluse, Denis Drygin, Kenna Anderes, Nanni Huser, Chris Proffitt, Joshua Bliesath, Mustapha Haddach, Michael K Schwaebe, David M Ryckman, William G Rice, Clemens Schmitt, Scott W Lowe, Ricky W Johnstone, Richard B Pearson, Grant A McArthur, Ross D Hannan, Megan J Bywater, Gretchen Poortinga, Elaine Sanij, Nadine Hein, Abigail Peck, Carleen Cullinane, Meaghan Wall, Leonie Cluse, Denis Drygin, Kenna Anderes, Nanni Huser, Chris Proffitt, Joshua Bliesath, Mustapha Haddach, Michael K Schwaebe, David M Ryckman, William G Rice, Clemens Schmitt, Scott W Lowe, Ricky W Johnstone, Richard B Pearson, Grant A McArthur, Ross D Hannan
Abstract
Increased transcription of ribosomal RNA genes (rDNA) by RNA Polymerase I is a common feature of human cancer, but whether it is required for the malignant phenotype remains unclear. We show that rDNA transcription can be therapeutically targeted with the small molecule CX-5461 to selectively kill B-lymphoma cells in vivo while maintaining a viable wild-type B cell population. The therapeutic effect is a consequence of nucleolar disruption and activation of p53-dependent apoptotic signaling. Human leukemia and lymphoma cell lines also show high sensitivity to inhibition of rDNA transcription that is dependent on p53 mutational status. These results identify selective inhibition of rDNA transcription as a therapeutic strategy for the cancer specific activation of p53 and treatment of hematologic malignancies.
Copyright © 2012 Elsevier Inc. All rights reserved.
Figures
![Figure 1. Regulation of Pol I Transcription…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3749732/bin/nihms481086f1.jpg)
![Figure 2. Reducing Pol I Transcription Rates…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3749732/bin/nihms481086f2.jpg)
![Figure 3. CX-5461 Induces Rapid, p53-Dependent, Apoptotic…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3749732/bin/nihms481086f3.jpg)
![Figure 4. CX-5461 Activates p53 via the…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3749732/bin/nihms481086f4.jpg)
![Figure 5. Therapeutic Administration of CX-5461 Selectively…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3749732/bin/nihms481086f5.jpg)
Figure 6. Therapeutic Administration of CX-5461, in…
Figure 6. Therapeutic Administration of CX-5461, in Contrast to γ-Irradiation, Does Not Kill Normal B…
Figure 7. Therapeutic Administration of CX-5461 Increases…
Figure 7. Therapeutic Administration of CX-5461 Increases Survival from Transplanted p53 Wild-type Eμ- Myc Lymphoma
(A) Kaplan-Meier…
Figure 8. Human Leukemia and Lymphoma Cell…
Figure 8. Human Leukemia and Lymphoma Cell Lines Treated with CX-5461
(A) The result of…
- Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling.Quin J, Chan KT, Devlin JR, Cameron DP, Diesch J, Cullinane C, Ahern J, Khot A, Hein N, George AJ, Hannan KM, Poortinga G, Sheppard KE, Khanna KK, Johnstone RW, Drygin D, McArthur GA, Pearson RB, Sanij E, Hannan RD. Quin J, et al. Oncotarget. 2016 Aug 2;7(31):49800-49818. doi: 10.18632/oncotarget.10452. Oncotarget. 2016. PMID: 27391441 Free PMC article.
- Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders.Calo E, Gu B, Bowen ME, Aryan F, Zalc A, Liang J, Flynn RA, Swigut T, Chang HY, Attardi LD, Wysocka J. Calo E, et al. Nature. 2018 Feb 1;554(7690):112-117. doi: 10.1038/nature25449. Epub 2018 Jan 24. Nature. 2018. PMID: 29364875 Free PMC article.
- Therapeutic Targeting of RNA Polymerase I With the Small-Molecule CX-5461 for Prevention of Arterial Injury-Induced Neointimal Hyperplasia.Ye Q, Pang S, Zhang W, Guo X, Wang J, Zhang Y, Liu Y, Wu X, Jiang F. Ye Q, et al. Arterioscler Thromb Vasc Biol. 2017 Mar;37(3):476-484. doi: 10.1161/ATVBAHA.116.308401. Epub 2017 Jan 5. Arterioscler Thromb Vasc Biol. 2017. PMID: 28062495
- The nucleolus as a fundamental regulator of the p53 response and a new target for cancer therapy.Woods SJ, Hannan KM, Pearson RB, Hannan RD. Woods SJ, et al. Biochim Biophys Acta. 2015 Jul;1849(7):821-9. doi: 10.1016/j.bbagrm.2014.10.007. Epub 2014 Nov 11. Biochim Biophys Acta. 2015. PMID: 25464032 Review.
- Targeting the nucleolus for cancer intervention.Quin JE, Devlin JR, Cameron D, Hannan KM, Pearson RB, Hannan RD. Quin JE, et al. Biochim Biophys Acta. 2014 Jun;1842(6):802-16. doi: 10.1016/j.bbadis.2013.12.009. Epub 2014 Jan 2. Biochim Biophys Acta. 2014. PMID: 24389329 Review.
- Structural and Functional Classification of G-Quadruplex Families within the Human Genome.Neupane A, Chariker JH, Rouchka EC. Neupane A, et al. Genes (Basel). 2023 Mar 4;14(3):645. doi: 10.3390/genes14030645. Genes (Basel). 2023. PMID: 36980918 Free PMC article.
- Current research on viral proteins that interact with fibrillarin.Decle-Carrasco S, Rodríguez-Piña AL, Rodríguez-Zapata LC, Castano E. Decle-Carrasco S, et al. Mol Biol Rep. 2023 Mar 16:1-13. doi: 10.1007/s11033-023-08343-2. Online ahead of print. Mol Biol Rep. 2023. PMID: 36928641 Free PMC article. Review.
- Ribosome biogenesis in disease: new players and therapeutic targets.Jiao L, Liu Y, Yu XY, Pan X, Zhang Y, Tu J, Song YH, Li Y. Jiao L, et al. Signal Transduct Target Ther. 2023 Jan 9;8(1):15. doi: 10.1038/s41392-022-01285-4. Signal Transduct Target Ther. 2023. PMID: 36617563 Free PMC article. Review.
- STAT3 potentiates RNA polymerase I-directed transcription and tumor growth by activating RPA34 expression.Zhang C, Wang J, Song X, Yu D, Guo B, Pang Y, Yin X, Zhao S, Deng H, Zhang S, Deng W. Zhang C, et al. Br J Cancer. 2023 Mar;128(5):766-782. doi: 10.1038/s41416-022-02098-6. Epub 2022 Dec 16. Br J Cancer. 2023. PMID: 36526675
- Methotrexate-Induced Liver Injury Is Associated with Oxidative Stress, Impaired Mitochondrial Respiration, and Endoplasmic Reticulum Stress In Vitro.Schmidt S, Messner CJ, Gaiser C, Hämmerli C, Suter-Dick L. Schmidt S, et al. Int J Mol Sci. 2022 Dec 1;23(23):15116. doi: 10.3390/ijms232315116. Int J Mol Sci. 2022. PMID: 36499436 Free PMC article.
- Research Support, Non-U.S. Gov't
- Animals
- Apoptosis
- Benzothiazoles / pharmacology
- DNA, Ribosomal / genetics
- Female
- Mice
- Mice, Transgenic
- Naphthyridines / pharmacology
- Neoplasms / genetics
- Neoplasms / metabolism*
- Neoplasms / pathology
- RNA Polymerase I / antagonists & inhibitors*
- RNA, Ribosomal / genetics
- Transcription, Genetic
- Tumor Suppressor Protein p53 / metabolism*
- Benzothiazoles
- CX 5461
- DNA, Ribosomal
- Naphthyridines
- RNA, Ribosomal
- Tumor Suppressor Protein p53
- RNA Polymerase I
- Full Text Sources
- Other Literature Sources
- Medical
- Molecular Biology Databases
- Research Materials
- Miscellaneous
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 6. Therapeutic Administration of CX-5461, in…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3749732/bin/nihms481086f6.jpg)
Figure 7. Therapeutic Administration of CX-5461 Increases…
Figure 7. Therapeutic Administration of CX-5461 Increases Survival from Transplanted p53 Wild-type Eμ- Myc Lymphoma
(A) Kaplan-Meier…
Figure 8. Human Leukemia and Lymphoma Cell…
Figure 8. Human Leukemia and Lymphoma Cell Lines Treated with CX-5461
(A) The result of…
- Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling.Quin J, Chan KT, Devlin JR, Cameron DP, Diesch J, Cullinane C, Ahern J, Khot A, Hein N, George AJ, Hannan KM, Poortinga G, Sheppard KE, Khanna KK, Johnstone RW, Drygin D, McArthur GA, Pearson RB, Sanij E, Hannan RD. Quin J, et al. Oncotarget. 2016 Aug 2;7(31):49800-49818. doi: 10.18632/oncotarget.10452. Oncotarget. 2016. PMID: 27391441 Free PMC article.
- Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders.Calo E, Gu B, Bowen ME, Aryan F, Zalc A, Liang J, Flynn RA, Swigut T, Chang HY, Attardi LD, Wysocka J. Calo E, et al. Nature. 2018 Feb 1;554(7690):112-117. doi: 10.1038/nature25449. Epub 2018 Jan 24. Nature. 2018. PMID: 29364875 Free PMC article.
- Therapeutic Targeting of RNA Polymerase I With the Small-Molecule CX-5461 for Prevention of Arterial Injury-Induced Neointimal Hyperplasia.Ye Q, Pang S, Zhang W, Guo X, Wang J, Zhang Y, Liu Y, Wu X, Jiang F. Ye Q, et al. Arterioscler Thromb Vasc Biol. 2017 Mar;37(3):476-484. doi: 10.1161/ATVBAHA.116.308401. Epub 2017 Jan 5. Arterioscler Thromb Vasc Biol. 2017. PMID: 28062495
- The nucleolus as a fundamental regulator of the p53 response and a new target for cancer therapy.Woods SJ, Hannan KM, Pearson RB, Hannan RD. Woods SJ, et al. Biochim Biophys Acta. 2015 Jul;1849(7):821-9. doi: 10.1016/j.bbagrm.2014.10.007. Epub 2014 Nov 11. Biochim Biophys Acta. 2015. PMID: 25464032 Review.
- Targeting the nucleolus for cancer intervention.Quin JE, Devlin JR, Cameron D, Hannan KM, Pearson RB, Hannan RD. Quin JE, et al. Biochim Biophys Acta. 2014 Jun;1842(6):802-16. doi: 10.1016/j.bbadis.2013.12.009. Epub 2014 Jan 2. Biochim Biophys Acta. 2014. PMID: 24389329 Review.
- Structural and Functional Classification of G-Quadruplex Families within the Human Genome.Neupane A, Chariker JH, Rouchka EC. Neupane A, et al. Genes (Basel). 2023 Mar 4;14(3):645. doi: 10.3390/genes14030645. Genes (Basel). 2023. PMID: 36980918 Free PMC article.
- Current research on viral proteins that interact with fibrillarin.Decle-Carrasco S, Rodríguez-Piña AL, Rodríguez-Zapata LC, Castano E. Decle-Carrasco S, et al. Mol Biol Rep. 2023 Mar 16:1-13. doi: 10.1007/s11033-023-08343-2. Online ahead of print. Mol Biol Rep. 2023. PMID: 36928641 Free PMC article. Review.
- Ribosome biogenesis in disease: new players and therapeutic targets.Jiao L, Liu Y, Yu XY, Pan X, Zhang Y, Tu J, Song YH, Li Y. Jiao L, et al. Signal Transduct Target Ther. 2023 Jan 9;8(1):15. doi: 10.1038/s41392-022-01285-4. Signal Transduct Target Ther. 2023. PMID: 36617563 Free PMC article. Review.
- STAT3 potentiates RNA polymerase I-directed transcription and tumor growth by activating RPA34 expression.Zhang C, Wang J, Song X, Yu D, Guo B, Pang Y, Yin X, Zhao S, Deng H, Zhang S, Deng W. Zhang C, et al. Br J Cancer. 2023 Mar;128(5):766-782. doi: 10.1038/s41416-022-02098-6. Epub 2022 Dec 16. Br J Cancer. 2023. PMID: 36526675
- Methotrexate-Induced Liver Injury Is Associated with Oxidative Stress, Impaired Mitochondrial Respiration, and Endoplasmic Reticulum Stress In Vitro.Schmidt S, Messner CJ, Gaiser C, Hämmerli C, Suter-Dick L. Schmidt S, et al. Int J Mol Sci. 2022 Dec 1;23(23):15116. doi: 10.3390/ijms232315116. Int J Mol Sci. 2022. PMID: 36499436 Free PMC article.
- Research Support, Non-U.S. Gov't
- Animals
- Apoptosis
- Benzothiazoles / pharmacology
- DNA, Ribosomal / genetics
- Female
- Mice
- Mice, Transgenic
- Naphthyridines / pharmacology
- Neoplasms / genetics
- Neoplasms / metabolism*
- Neoplasms / pathology
- RNA Polymerase I / antagonists & inhibitors*
- RNA, Ribosomal / genetics
- Transcription, Genetic
- Tumor Suppressor Protein p53 / metabolism*
- Benzothiazoles
- CX 5461
- DNA, Ribosomal
- Naphthyridines
- RNA, Ribosomal
- Tumor Suppressor Protein p53
- RNA Polymerase I
- Full Text Sources
- Other Literature Sources
- Medical
- Molecular Biology Databases
- Research Materials
- Miscellaneous
NCBI Literature Resources
The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.
National Library of Medicine
8600 Rockville Pike
Bethesda, MD 20894
![Figure 7. Therapeutic Administration of CX-5461 Increases…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3749732/bin/nihms481086f7.jpg)
Figure 8. Human Leukemia and Lymphoma Cell…
Figure 8. Human Leukemia and Lymphoma Cell Lines Treated with CX-5461
(A) The result of…
- Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling.Quin J, Chan KT, Devlin JR, Cameron DP, Diesch J, Cullinane C, Ahern J, Khot A, Hein N, George AJ, Hannan KM, Poortinga G, Sheppard KE, Khanna KK, Johnstone RW, Drygin D, McArthur GA, Pearson RB, Sanij E, Hannan RD. Quin J, et al. Oncotarget. 2016 Aug 2;7(31):49800-49818. doi: 10.18632/oncotarget.10452. Oncotarget. 2016. PMID: 27391441 Free PMC article.
- Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders.Calo E, Gu B, Bowen ME, Aryan F, Zalc A, Liang J, Flynn RA, Swigut T, Chang HY, Attardi LD, Wysocka J. Calo E, et al. Nature. 2018 Feb 1;554(7690):112-117. doi: 10.1038/nature25449. Epub 2018 Jan 24. Nature. 2018. PMID: 29364875 Free PMC article.
- Therapeutic Targeting of RNA Polymerase I With the Small-Molecule CX-5461 for Prevention of Arterial Injury-Induced Neointimal Hyperplasia.Ye Q, Pang S, Zhang W, Guo X, Wang J, Zhang Y, Liu Y, Wu X, Jiang F. Ye Q, et al. Arterioscler Thromb Vasc Biol. 2017 Mar;37(3):476-484. doi: 10.1161/ATVBAHA.116.308401. Epub 2017 Jan 5. Arterioscler Thromb Vasc Biol. 2017. PMID: 28062495
- The nucleolus as a fundamental regulator of the p53 response and a new target for cancer therapy.Woods SJ, Hannan KM, Pearson RB, Hannan RD. Woods SJ, et al. Biochim Biophys Acta. 2015 Jul;1849(7):821-9. doi: 10.1016/j.bbagrm.2014.10.007. Epub 2014 Nov 11. Biochim Biophys Acta. 2015. PMID: 25464032 Review.
- Targeting the nucleolus for cancer intervention.Quin JE, Devlin JR, Cameron D, Hannan KM, Pearson RB, Hannan RD. Quin JE, et al. Biochim Biophys Acta. 2014 Jun;1842(6):802-16. doi: 10.1016/j.bbadis.2013.12.009. Epub 2014 Jan 2. Biochim Biophys Acta. 2014. PMID: 24389329 Review.
- Structural and Functional Classification of G-Quadruplex Families within the Human Genome.Neupane A, Chariker JH, Rouchka EC. Neupane A, et al. Genes (Basel). 2023 Mar 4;14(3):645. doi: 10.3390/genes14030645. Genes (Basel). 2023. PMID: 36980918 Free PMC article.
- Current research on viral proteins that interact with fibrillarin.Decle-Carrasco S, Rodríguez-Piña AL, Rodríguez-Zapata LC, Castano E. Decle-Carrasco S, et al. Mol Biol Rep. 2023 Mar 16:1-13. doi: 10.1007/s11033-023-08343-2. Online ahead of print. Mol Biol Rep. 2023. PMID: 36928641 Free PMC article. Review.
- Ribosome biogenesis in disease: new players and therapeutic targets.Jiao L, Liu Y, Yu XY, Pan X, Zhang Y, Tu J, Song YH, Li Y. Jiao L, et al. Signal Transduct Target Ther. 2023 Jan 9;8(1):15. doi: 10.1038/s41392-022-01285-4. Signal Transduct Target Ther. 2023. PMID: 36617563 Free PMC article. Review.
- STAT3 potentiates RNA polymerase I-directed transcription and tumor growth by activating RPA34 expression.Zhang C, Wang J, Song X, Yu D, Guo B, Pang Y, Yin X, Zhao S, Deng H, Zhang S, Deng W. Zhang C, et al. Br J Cancer. 2023 Mar;128(5):766-782. doi: 10.1038/s41416-022-02098-6. Epub 2022 Dec 16. Br J Cancer. 2023. PMID: 36526675
- Methotrexate-Induced Liver Injury Is Associated with Oxidative Stress, Impaired Mitochondrial Respiration, and Endoplasmic Reticulum Stress In Vitro.Schmidt S, Messner CJ, Gaiser C, Hämmerli C, Suter-Dick L. Schmidt S, et al. Int J Mol Sci. 2022 Dec 1;23(23):15116. doi: 10.3390/ijms232315116. Int J Mol Sci. 2022. PMID: 36499436 Free PMC article.
- Research Support, Non-U.S. Gov't
- Animals
- Apoptosis
- Benzothiazoles / pharmacology
- DNA, Ribosomal / genetics
- Female
- Mice
- Mice, Transgenic
- Naphthyridines / pharmacology
- Neoplasms / genetics
- Neoplasms / metabolism*
- Neoplasms / pathology
- RNA Polymerase I / antagonists & inhibitors*
- RNA, Ribosomal / genetics
- Transcription, Genetic
- Tumor Suppressor Protein p53 / metabolism*
- Benzothiazoles
- CX 5461
- DNA, Ribosomal
- Naphthyridines
- RNA, Ribosomal
- Tumor Suppressor Protein p53
- RNA Polymerase I
- Full Text Sources
- Other Literature Sources
- Medical
- Molecular Biology Databases
- Research Materials
- Miscellaneous
![Figure 8. Human Leukemia and Lymphoma Cell…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3749732/bin/nihms481086f8.jpg)
Source: PubMed