Mitochondrial apoptotic priming is a key determinant of cell fate upon p53 restoration.
Mitochondrial apoptotic priming is a key determinant of cell fate upon p53 restoration.
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DOI：
10.1073/pnas.2019740118
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发表时间：
2021-06-08
影响因子：
11.1
通讯作者：
Jacks T
中科院分区：
文献类型：
--
作者：
Sánchez-Rivera FJ;Ryan J;Soto-Feliciano YM;Clare Beytagh M;Xuan L;Feldser DM;Hemann MT;Zamudio J;Dimitrova N;Letai A;Jacks T
长期以来，已经观察到p53的活化可以产生两种主要的细胞命运：凋亡性细胞死亡或细胞周期停滞。然而，是什么决定了这种细胞的命运仍有待充分阐明。在这里，我们表明，线粒体启动前激活p53的状态可以决定细胞的命运。高度致敏的细胞致力于凋亡，而较少致敏的细胞致力于细胞周期停滞。我们发现，在任何一个方向的启动调制可以改变细胞的命运;增加启动不良的细胞产生凋亡，而减少启动高度引发的细胞产生逮捕。增加启动的药物强制凋亡命运，这表明了一种p53非依赖性策略，用于增强通过p53杀死的癌症化疗药物的功效。在已建立的肿瘤中p53的再活化通常导致两种细胞命运之一，细胞周期停滞或凋亡，但仍不清楚这种细胞命运是如何确定的。我们假设在p53重新激活之前高线粒体引发将导致细胞凋亡，而低引发将导致存活和细胞周期停滞。使用一组Kras驱动的p53可激活的细胞系，这些细胞系来自肺腺癌和肉瘤的基因工程小鼠模型（两者在p53恢复后都经历细胞周期停滞），以及淋巴瘤（相反经历细胞凋亡），我们表明线粒体细胞凋亡引发的水平是p53再激活结果的关键决定因素。具有高初始引发的细胞（例如，淋巴瘤）缺乏足够的储备抗凋亡能力，并在p53恢复后发生凋亡。强制BCL-2或BCL-XL表达减少引发并导致存活和细胞周期停滞。具有低初始引发的细胞（例如，肺腺癌和肉瘤）存活，并在细胞周期中继续停滞。当使用遗传（BCL-2或BCL-XL缺失或BAD过表达）或药理学（navitoclax）手段通过抑制其抗凋亡蛋白引发时，在体外和体内p53恢复后导致凋亡。这些数据表明，线粒体凋亡引发是p53激活后细胞命运的关键决定因素。此外，有可能使用增加凋亡引发的p53非依赖性药物（包括BH 3模拟药物）在引发较少的细胞中在p53激活后强制凋亡细胞命运。
It has long been observed that activation of p53 can yield two main cell fates: either apoptotic cell death or cell cycle arrest. However, what determines this cell fate remains to be fully elucidated. Here we show that the state of mitochondrial priming prior to activation of p53 can determine cell fate. Highly primed cells commit to apoptosis, while less-primed cells commit to cell cycle arrest. We show that modulation of priming in either direction can alter cell fate; increasing priming in poorly primed cells yields apoptosis, while decreasing priming in highly primed cells yields arrest. Drugs that increase priming enforce an apoptotic fate, suggesting a p53-independent strategy for augmenting efficacy of cancer chemotherapy drugs that kill via p53. 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.
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