Mitochondrial apoptotic priming is a key determinant of cell fate upon p53 restoration
<jats:p>Reactivation of p53 in established tumors typically results in one of two cell fates, cell cycle arrest or apoptosis, but it remains unclear how this cell fate is determined. We hypothesized that high mitochondrial priming prior to p53 reactivation would lead to apoptosis, while low pr...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Proceedings of the National Academy of Sciences
2021
|
| Online Access: | https://hdl.handle.net/1721.1/135549 |
| _version_ | 1826198220114493440 |
|---|---|
| author | Sánchez-Rivera, Francisco J Ryan, Jeremy Soto-Feliciano, Yadira M Clare Beytagh, Mary Xuan, Lucius Feldser, David M Hemann, Michael T Zamudio, Jesse Dimitrova, Nadya Letai, Anthony Jacks, Tyler |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Sánchez-Rivera, Francisco J Ryan, Jeremy Soto-Feliciano, Yadira M Clare Beytagh, Mary Xuan, Lucius Feldser, David M Hemann, Michael T Zamudio, Jesse Dimitrova, Nadya Letai, Anthony Jacks, Tyler |
| author_sort | Sánchez-Rivera, Francisco J |
| collection | MIT |
| description | <jats:p>Reactivation of p53 in established tumors typically results in one of two cell fates, cell cycle arrest or apoptosis, but it remains unclear how this cell fate is determined. We hypothesized that high mitochondrial priming prior to p53 reactivation would lead to apoptosis, while low priming would lead to survival and cell cycle arrest. Using a panel of Kras-driven, p53 restorable cell lines derived from genetically engineered mouse models of lung adenocarcinoma and sarcoma (both of which undergo cell cycle arrest upon p53 restoration), as well as lymphoma (which instead undergo apoptosis), we show that the level of mitochondrial apoptotic priming is a critical determinant of p53 reactivation outcome. Cells with high initial priming (e.g., lymphomas) lacked sufficient reserve antiapoptotic capacity and underwent apoptosis after p53 restoration. Forced BCL-2 or BCL-XL expression reduced priming and resulted in survival and cell cycle arrest. Cells with low initial priming (e.g., lung adenocarcinoma and sarcoma) survived and proceeded to arrest in the cell cycle. When primed by inhibition of their antiapoptotic proteins using genetic (BCL-2 or BCL-XL deletion or BAD overexpression) or pharmacologic (navitoclax) means, apoptosis resulted upon p53 restoration in vitro and in vivo. These data demonstrate that mitochondrial apoptotic priming is a key determining factor of cell fate upon p53 activation. Moreover, it is possible to enforce apoptotic cell fate following p53 activation in less primed cells using p53-independent drugs that increase apoptotic priming, including BH3 mimetic drugs.</jats:p> |
| first_indexed | 2024-09-23T11:01:18Z |
| format | Article |
| id | mit-1721.1/135549 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T11:01:18Z |
| publishDate | 2021 |
| publisher | Proceedings of the National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/1355492023-09-15T18:15:38Z Mitochondrial apoptotic priming is a key determinant of cell fate upon p53 restoration Sánchez-Rivera, Francisco J Ryan, Jeremy Soto-Feliciano, Yadira M Clare Beytagh, Mary Xuan, Lucius Feldser, David M Hemann, Michael T Zamudio, Jesse Dimitrova, Nadya Letai, Anthony Jacks, Tyler Koch Institute for Integrative Cancer Research at MIT Massachusetts Institute of Technology. Department of Biology Howard Hughes Medical Institute <jats:p>Reactivation of p53 in established tumors typically results in one of two cell fates, cell cycle arrest or apoptosis, but it remains unclear how this cell fate is determined. We hypothesized that high mitochondrial priming prior to p53 reactivation would lead to apoptosis, while low priming would lead to survival and cell cycle arrest. Using a panel of Kras-driven, p53 restorable cell lines derived from genetically engineered mouse models of lung adenocarcinoma and sarcoma (both of which undergo cell cycle arrest upon p53 restoration), as well as lymphoma (which instead undergo apoptosis), we show that the level of mitochondrial apoptotic priming is a critical determinant of p53 reactivation outcome. Cells with high initial priming (e.g., lymphomas) lacked sufficient reserve antiapoptotic capacity and underwent apoptosis after p53 restoration. Forced BCL-2 or BCL-XL expression reduced priming and resulted in survival and cell cycle arrest. Cells with low initial priming (e.g., lung adenocarcinoma and sarcoma) survived and proceeded to arrest in the cell cycle. When primed by inhibition of their antiapoptotic proteins using genetic (BCL-2 or BCL-XL deletion or BAD overexpression) or pharmacologic (navitoclax) means, apoptosis resulted upon p53 restoration in vitro and in vivo. These data demonstrate that mitochondrial apoptotic priming is a key determining factor of cell fate upon p53 activation. Moreover, it is possible to enforce apoptotic cell fate following p53 activation in less primed cells using p53-independent drugs that increase apoptotic priming, including BH3 mimetic drugs.</jats:p> 2021-10-27T20:23:58Z 2021-10-27T20:23:58Z 2021 2021-07-16T15:07:36Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/135549 en 10.1073/pnas.2019740118 Proceedings of the National Academy of Sciences of the United States of America Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Proceedings of the National Academy of Sciences PNAS |
| spellingShingle | Sánchez-Rivera, Francisco J Ryan, Jeremy Soto-Feliciano, Yadira M Clare Beytagh, Mary Xuan, Lucius Feldser, David M Hemann, Michael T Zamudio, Jesse Dimitrova, Nadya Letai, Anthony Jacks, Tyler Mitochondrial apoptotic priming is a key determinant of cell fate upon p53 restoration |
| title | Mitochondrial apoptotic priming is a key determinant of cell fate upon p53 restoration |
| title_full | Mitochondrial apoptotic priming is a key determinant of cell fate upon p53 restoration |
| title_fullStr | Mitochondrial apoptotic priming is a key determinant of cell fate upon p53 restoration |
| title_full_unstemmed | Mitochondrial apoptotic priming is a key determinant of cell fate upon p53 restoration |
| title_short | Mitochondrial apoptotic priming is a key determinant of cell fate upon p53 restoration |
| title_sort | mitochondrial apoptotic priming is a key determinant of cell fate upon p53 restoration |
| url | https://hdl.handle.net/1721.1/135549 |
| work_keys_str_mv | AT sanchezriverafranciscoj mitochondrialapoptoticprimingisakeydeterminantofcellfateuponp53restoration AT ryanjeremy mitochondrialapoptoticprimingisakeydeterminantofcellfateuponp53restoration AT sotofelicianoyadiram mitochondrialapoptoticprimingisakeydeterminantofcellfateuponp53restoration AT clarebeytaghmary mitochondrialapoptoticprimingisakeydeterminantofcellfateuponp53restoration AT xuanlucius mitochondrialapoptoticprimingisakeydeterminantofcellfateuponp53restoration AT feldserdavidm mitochondrialapoptoticprimingisakeydeterminantofcellfateuponp53restoration AT hemannmichaelt mitochondrialapoptoticprimingisakeydeterminantofcellfateuponp53restoration AT zamudiojesse mitochondrialapoptoticprimingisakeydeterminantofcellfateuponp53restoration AT dimitrovanadya mitochondrialapoptoticprimingisakeydeterminantofcellfateuponp53restoration AT letaianthony mitochondrialapoptoticprimingisakeydeterminantofcellfateuponp53restoration AT jackstyler mitochondrialapoptoticprimingisakeydeterminantofcellfateuponp53restoration |