Molecular modelling of the FOXO4-TP53 interaction to design senolytic peptides for the elimination of senescent cancer cells
Background: Senescent cells accumulate in tissues over time as part of the natural ageing process and the removal of senescent cells has shown promise for alleviating many different age-related diseases in mice. Cancer is an age-associated disease and there are numerous mechanisms driving cellular s...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-11-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396421004394 |
| _version_ | 1818826612239499264 |
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| author | Hillary H. Le Suleyman S. Cinaroglu Elise C. Manalo Aysegul Ors Michelle M. Gomes Burcin Duan Sahbaz Karla Bonic Carlos A. Origel Marmolejo Arnaud Quentel Justin S. Plaut Taryn E. Kawashima E. Sila Ozdemir Sanjay V. Malhotra Yavuz Ahiska Ugur Sezerman Gunseli Bayram Akcapinar Joshua C. Saldivar Emel Timucin Jared M. Fischer |
| author_facet | Hillary H. Le Suleyman S. Cinaroglu Elise C. Manalo Aysegul Ors Michelle M. Gomes Burcin Duan Sahbaz Karla Bonic Carlos A. Origel Marmolejo Arnaud Quentel Justin S. Plaut Taryn E. Kawashima E. Sila Ozdemir Sanjay V. Malhotra Yavuz Ahiska Ugur Sezerman Gunseli Bayram Akcapinar Joshua C. Saldivar Emel Timucin Jared M. Fischer |
| author_sort | Hillary H. Le |
| collection | DOAJ |
| description | Background: Senescent cells accumulate in tissues over time as part of the natural ageing process and the removal of senescent cells has shown promise for alleviating many different age-related diseases in mice. Cancer is an age-associated disease and there are numerous mechanisms driving cellular senescence in cancer that can be detrimental to recovery. Thus, it would be beneficial to develop a senolytic that acts not only on ageing cells but also senescent cancer cells to prevent cancer recurrence or progression. Methods: We used molecular modelling to develop a series of rationally designed peptides to mimic and target FOXO4 disrupting the FOXO4-TP53 interaction and releasing TP53 to induce apoptosis. We then tested these peptides as senolytic agents for the elimination of senescent cells both in cell culture and in vivo. Findings: Here we show that these peptides can act as senolytics for eliminating senescent human cancer cells both in cell culture and in orthotopic mouse models. We then further characterized one peptide, ES2, showing that it disrupts FOXO4-TP53 foci, activates TP53 mediated apoptosis and preferentially binds FOXO4 compared to TP53. Next, we show that intratumoural delivery of ES2 plus a BRAF inhibitor results in a significant increase in apoptosis and a survival advantage in mouse models of melanoma. Finally, we show that repeated systemic delivery of ES2 to older mice results in reduced senescent cell numbers in the liver with minimal toxicity. Interpretation: Taken together, our results reveal that peptides can be generated to specifically target and eliminate FOXO4+ senescent cancer cells, which has implications for eradicating residual disease and as a combination therapy for frontline treatment of cancer. Funding: This work was supported by the Cancer Early Detection Advanced Research Center at Oregon Health & Science University. |
| first_indexed | 2024-12-19T00:30:26Z |
| format | Article |
| id | doaj.art-e47bd46165a546c3a103052aa9b58199 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-19T00:30:26Z |
| publishDate | 2021-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-e47bd46165a546c3a103052aa9b581992022-12-21T20:45:07ZengElsevierEBioMedicine2352-39642021-11-0173103646Molecular modelling of the FOXO4-TP53 interaction to design senolytic peptides for the elimination of senescent cancer cellsHillary H. Le0Suleyman S. Cinaroglu1Elise C. Manalo2Aysegul Ors3Michelle M. Gomes4Burcin Duan Sahbaz5Karla Bonic6Carlos A. Origel Marmolejo7Arnaud Quentel8Justin S. Plaut9Taryn E. Kawashima10E. Sila Ozdemir11Sanjay V. Malhotra12Yavuz Ahiska13Ugur Sezerman14Gunseli Bayram Akcapinar15Joshua C. Saldivar16Emel Timucin17Jared M. Fischer18Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, USAInstitute of Health Sciences, Acibadem Mehmet Ali Aydinlar University, Atasehir Istanbul 34752, Turkey; Eternans Ltd., UKCancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, USACancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, USACancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, USAEternans Ltd., UKCancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, USACancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, USACancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, USACancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, USA; Dept of Bioengineering, University of California San Diego, USACancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, USACancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, USACancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, USA; Dept of Cell, Developmental and Cancer Biology, Oregon Health & Science University, USAEternans Ltd., UKEternans Ltd., UK; School of Medicine, Acibadem Mehmet Ali Aydinlar University, Atasehir Istanbul 34752, TurkeyInstitute of Health Sciences, Acibadem Mehmet Ali Aydinlar University, Atasehir Istanbul 34752, Turkey; Eternans Ltd., UKCancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, USA; Division of Oncological Sciences, Knight Cancer Institute, Oregon Health & Science University, USAEternans Ltd., UK; School of Medicine, Acibadem Mehmet Ali Aydinlar University, Atasehir Istanbul 34752, TurkeyCancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University, USA; Dept of Molecular and Medical Genetics, Oregon Health & Science University, USA; Corresponding author.Background: Senescent cells accumulate in tissues over time as part of the natural ageing process and the removal of senescent cells has shown promise for alleviating many different age-related diseases in mice. Cancer is an age-associated disease and there are numerous mechanisms driving cellular senescence in cancer that can be detrimental to recovery. Thus, it would be beneficial to develop a senolytic that acts not only on ageing cells but also senescent cancer cells to prevent cancer recurrence or progression. Methods: We used molecular modelling to develop a series of rationally designed peptides to mimic and target FOXO4 disrupting the FOXO4-TP53 interaction and releasing TP53 to induce apoptosis. We then tested these peptides as senolytic agents for the elimination of senescent cells both in cell culture and in vivo. Findings: Here we show that these peptides can act as senolytics for eliminating senescent human cancer cells both in cell culture and in orthotopic mouse models. We then further characterized one peptide, ES2, showing that it disrupts FOXO4-TP53 foci, activates TP53 mediated apoptosis and preferentially binds FOXO4 compared to TP53. Next, we show that intratumoural delivery of ES2 plus a BRAF inhibitor results in a significant increase in apoptosis and a survival advantage in mouse models of melanoma. Finally, we show that repeated systemic delivery of ES2 to older mice results in reduced senescent cell numbers in the liver with minimal toxicity. Interpretation: Taken together, our results reveal that peptides can be generated to specifically target and eliminate FOXO4+ senescent cancer cells, which has implications for eradicating residual disease and as a combination therapy for frontline treatment of cancer. Funding: This work was supported by the Cancer Early Detection Advanced Research Center at Oregon Health & Science University.http://www.sciencedirect.com/science/article/pii/S2352396421004394SenolyticFOXO4TP53Cancer |
| spellingShingle | Hillary H. Le Suleyman S. Cinaroglu Elise C. Manalo Aysegul Ors Michelle M. Gomes Burcin Duan Sahbaz Karla Bonic Carlos A. Origel Marmolejo Arnaud Quentel Justin S. Plaut Taryn E. Kawashima E. Sila Ozdemir Sanjay V. Malhotra Yavuz Ahiska Ugur Sezerman Gunseli Bayram Akcapinar Joshua C. Saldivar Emel Timucin Jared M. Fischer Molecular modelling of the FOXO4-TP53 interaction to design senolytic peptides for the elimination of senescent cancer cells EBioMedicine Senolytic FOXO4 TP53 Cancer |
| title | Molecular modelling of the FOXO4-TP53 interaction to design senolytic peptides for the elimination of senescent cancer cells |
| title_full | Molecular modelling of the FOXO4-TP53 interaction to design senolytic peptides for the elimination of senescent cancer cells |
| title_fullStr | Molecular modelling of the FOXO4-TP53 interaction to design senolytic peptides for the elimination of senescent cancer cells |
| title_full_unstemmed | Molecular modelling of the FOXO4-TP53 interaction to design senolytic peptides for the elimination of senescent cancer cells |
| title_short | Molecular modelling of the FOXO4-TP53 interaction to design senolytic peptides for the elimination of senescent cancer cells |
| title_sort | molecular modelling of the foxo4 tp53 interaction to design senolytic peptides for the elimination of senescent cancer cells |
| topic | Senolytic FOXO4 TP53 Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2352396421004394 |
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