p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism
Abstract The p53 tumor suppressor regulates multiple context-dependent tumor suppressive programs. Although p53 is mutated in ~90% of small cell lung cancer (SCLC) tumors, how p53 mediates tumor suppression in this context is unknown. Here, using a mouse model of SCLC in which endogenous p53 express...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-40161-9 |
| _version_ | 1827895074455814144 |
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| author | Jonuelle Acosta Qinglan Li Nelson F. Freeburg Nivitha Murali Alexandra Indeglia Grant P. Grothusen Michelle Cicchini Hung Mai Amy C. Gladstein Keren M. Adler Katherine R. Doerig Jinyang Li Miguel Ruiz-Torres Kimberly L. Manning Ben Z. Stanger Luca Busino Maureen Murphy Liling Wan David M. Feldser |
| author_facet | Jonuelle Acosta Qinglan Li Nelson F. Freeburg Nivitha Murali Alexandra Indeglia Grant P. Grothusen Michelle Cicchini Hung Mai Amy C. Gladstein Keren M. Adler Katherine R. Doerig Jinyang Li Miguel Ruiz-Torres Kimberly L. Manning Ben Z. Stanger Luca Busino Maureen Murphy Liling Wan David M. Feldser |
| author_sort | Jonuelle Acosta |
| collection | DOAJ |
| description | Abstract The p53 tumor suppressor regulates multiple context-dependent tumor suppressive programs. Although p53 is mutated in ~90% of small cell lung cancer (SCLC) tumors, how p53 mediates tumor suppression in this context is unknown. Here, using a mouse model of SCLC in which endogenous p53 expression can be conditionally and temporally regulated, we show that SCLC tumors maintain a requirement for p53 inactivation. However, we identify tumor subtype heterogeneity between SCLC tumors such that p53 reactivation induces senescence in a subset of tumors, while in others, p53 induces necrosis. We pinpoint cyclophilins as critical determinants of a p53-induced transcriptional program that is specific to SCLC tumors and cell lines poised to undergo p53-mediated necrosis. Importantly, inhibition of cyclophilin isomerase activity, or genetic ablation of specific cyclophilin genes, suppresses p53-mediated necrosis by limiting p53 transcriptional output without impacting p53 chromatin binding. Our study demonstrates that intertumoral heterogeneity in SCLC influences the biological response to p53 restoration, describes a cyclophilin-dependent mechanism of p53-regulated cell death, and uncovers putative mechanisms for the treatment of this most-recalcitrant tumor type. |
| first_indexed | 2024-03-12T22:16:28Z |
| format | Article |
| id | doaj.art-ff845a6444d4462dbb8f4fdf61c394b3 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-12T22:16:28Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-ff845a6444d4462dbb8f4fdf61c394b32023-07-23T11:18:34ZengNature PortfolioNature Communications2041-17232023-07-0114111810.1038/s41467-023-40161-9p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanismJonuelle Acosta0Qinglan Li1Nelson F. Freeburg2Nivitha Murali3Alexandra Indeglia4Grant P. Grothusen5Michelle Cicchini6Hung Mai7Amy C. Gladstein8Keren M. Adler9Katherine R. Doerig10Jinyang Li11Miguel Ruiz-Torres12Kimberly L. Manning13Ben Z. Stanger14Luca Busino15Maureen Murphy16Liling Wan17David M. Feldser18Department of Cancer Biology, Perelman School of Medicine, University of PennsylvaniaDepartment of Cancer Biology, Perelman School of Medicine, University of PennsylvaniaDepartment of Cancer Biology, Perelman School of Medicine, University of PennsylvaniaDepartment of Cancer Biology, Perelman School of Medicine, University of PennsylvaniaBiochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of PennsylvaniaDepartment of Cancer Biology, Perelman School of Medicine, University of PennsylvaniaDepartment of Cancer Biology, Perelman School of Medicine, University of PennsylvaniaDepartment of Cancer Biology, Perelman School of Medicine, University of PennsylvaniaDepartment of Cancer Biology, Perelman School of Medicine, University of PennsylvaniaDepartment of Cancer Biology, Perelman School of Medicine, University of PennsylvaniaDepartment of Cancer Biology, Perelman School of Medicine, University of PennsylvaniaDepartment of Cancer Biology, Perelman School of Medicine, University of PennsylvaniaDepartment of Cancer Biology, Perelman School of Medicine, University of PennsylvaniaDepartment of Cancer Biology, Perelman School of Medicine, University of PennsylvaniaCell and Molecular Biology Graduate Group, Perelman School of Medicine, University of PennsylvaniaDepartment of Cancer Biology, Perelman School of Medicine, University of PennsylvaniaCell and Molecular Biology Graduate Group, Perelman School of Medicine, University of PennsylvaniaDepartment of Cancer Biology, Perelman School of Medicine, University of PennsylvaniaDepartment of Cancer Biology, Perelman School of Medicine, University of PennsylvaniaAbstract The p53 tumor suppressor regulates multiple context-dependent tumor suppressive programs. Although p53 is mutated in ~90% of small cell lung cancer (SCLC) tumors, how p53 mediates tumor suppression in this context is unknown. Here, using a mouse model of SCLC in which endogenous p53 expression can be conditionally and temporally regulated, we show that SCLC tumors maintain a requirement for p53 inactivation. However, we identify tumor subtype heterogeneity between SCLC tumors such that p53 reactivation induces senescence in a subset of tumors, while in others, p53 induces necrosis. We pinpoint cyclophilins as critical determinants of a p53-induced transcriptional program that is specific to SCLC tumors and cell lines poised to undergo p53-mediated necrosis. Importantly, inhibition of cyclophilin isomerase activity, or genetic ablation of specific cyclophilin genes, suppresses p53-mediated necrosis by limiting p53 transcriptional output without impacting p53 chromatin binding. Our study demonstrates that intertumoral heterogeneity in SCLC influences the biological response to p53 restoration, describes a cyclophilin-dependent mechanism of p53-regulated cell death, and uncovers putative mechanisms for the treatment of this most-recalcitrant tumor type.https://doi.org/10.1038/s41467-023-40161-9 |
| spellingShingle | Jonuelle Acosta Qinglan Li Nelson F. Freeburg Nivitha Murali Alexandra Indeglia Grant P. Grothusen Michelle Cicchini Hung Mai Amy C. Gladstein Keren M. Adler Katherine R. Doerig Jinyang Li Miguel Ruiz-Torres Kimberly L. Manning Ben Z. Stanger Luca Busino Maureen Murphy Liling Wan David M. Feldser p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism Nature Communications |
| title | p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism |
| title_full | p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism |
| title_fullStr | p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism |
| title_full_unstemmed | p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism |
| title_short | p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism |
| title_sort | p53 restoration in small cell lung cancer identifies a latent cyclophilin dependent necrosis mechanism |
| url | https://doi.org/10.1038/s41467-023-40161-9 |
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