p53 restoration in small cell lung cancer identifies a latent cyclophilin-dependent necrosis mechanism

被引:6
作者
Acosta, Jonuelle [1 ,2 ]
Li, Qinglan [1 ]
Freeburg, Nelson F. [1 ,2 ]
Murali, Nivitha [1 ]
Indeglia, Alexandra [3 ]
Grothusen, Grant P. [1 ,2 ]
Cicchini, Michelle [1 ]
Mai, Hung [1 ]
Gladstein, Amy C. [1 ,2 ]
Adler, Keren M. [1 ,2 ]
Doerig, Katherine R. [1 ,2 ]
Li, Jinyang [1 ]
Ruiz-Torres, Miguel [1 ]
Manning, Kimberly L. [1 ]
Stanger, Ben Z. [2 ,4 ]
Busino, Luca [1 ,2 ,4 ]
Murphy, Maureen [2 ,5 ]
Wan, Liling [1 ,2 ,4 ]
Feldser, David M. [1 ,2 ,4 ]
机构
[1] Univ Penn, Perelman Sch Med, Dept Canc Biol, Philadelphia, PA USA
[2] Univ Penn, Perelman Sch Med, Cell & Mol Biol Grad Grp, Philadelphia, PA USA
[3] Univ Penn, Perelman Sch Med, Biochem & Mol Biophys Grad Grp, Philadelphia, PA USA
[4] Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA USA
[5] Wistar Inst Anat & Biol, Program Mol & Cellular Oncogenesis, Philadelphia, PA USA
关键词
MITOCHONDRIAL PERMEABILITY TRANSITION; TUMOR SUPPRESSION; BINDING; EXPRESSION; LANDSCAPE; INACTIVATION; PROGRESSION; INHIBITION; SENESCENCE; ISOMERASE;
D O I
10.1038/s41467-023-40161-9
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The p53 tumor suppressor regulates multiple context-dependent tumor suppressive programs. Although p53 is mutated in similar to 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. p53 inactivation is nearly universal in small-cell lung cancer (SCLC), but its tumor suppressive role in this cancer type is poorly understood. Here the authors show that intertumoral heterogeneity in SCLC influences the biological mechanisms of p53-mediated tumor suppression and identify a role for cyclophilins in p53-dependent necrotic cell death.
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页数:18
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