NRF2 Is a Major Target of ARF in p53-Independent Tumor Suppression.
NRF2 Is a Major Target of ARF in p53-Independent Tumor Suppression.
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DOI：
10.1016/j.molcel.2017.09.009
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发表时间：
2017-10-05
期刊：
影响因子：
16
通讯作者：
Gu W
中科院分区：
文献类型：
--
作者：
Chen D;Tavana O;Chu B;Erber L;Chen Y;Baer R;Gu W
尽管ARF可以通过激活p53功能来抑制肿瘤生长，但其独立于p53抑制肿瘤生长的机制尚不清楚。在这里，我们确定ARF作为核因子E2相关因子2（NRF 2）的关键调节因子，通过复杂的纯化。ARF抑制NRF 2转录激活其靶基因的能力，包括SLC 7A 11，SLC 7A 11是调节活性氧（ROS）诱导的铁凋亡的胱氨酸/谷氨酸反向转运蛋白的组分。因此，ARF表达以不依赖于p53的方式使细胞对铁凋亡敏感，而ARF耗竭诱导NRF 2活化并促进癌细胞对氧化应激的应答存活。此外，在小鼠异种移植模型中，ARF诱导p53非依赖性肿瘤生长抑制的能力在NRF 2过表达时显著消除。这些结果表明，NRF 2是ARF的p53非依赖性肿瘤抑制的主要靶点，也表明ARF-NRF 2相互作用作为氧化应激反应的新检查点。Chen等，确定ARF是NRF 2介导的SLC 7A 11激活的关键调节因子，SLC 7A 11是调节活性氧自由基（ROS）诱导的铁细胞凋亡的胱氨酸/谷氨酸反向转运蛋白的组成部分。他们表明，ARF-NRF 2相互作用对于P53非依赖性铁凋亡和ARF诱导的肿瘤抑制至关重要。
Although ARF can suppress tumor growth by activating p53 function, the mechanisms by which it suppresses tumor growth independently of p53 are not well understood. Here, we identified ARF as a key regulator of nuclear factor-E2-related factor 2 (NRF2) through complex purification. ARF inhibits the ability of NRF2 to transcriptionally activate its target genes, including SLC7A11, a component of the cystine/glutamate antiporter that regulates reactive oxygen species (ROS)-induced ferroptosis. As a consequence, ARF expression sensitizes cells to ferroptosis in a p53-independent manner while ARF depletion induces NRF2 activation and promotes cancer cell survival in response to oxidative stress. Moreover, the ability of ARF to induce p53-independent tumor growth suppression in mouse xenograft models is significantly abrogated upon NRF2 overexpression. These results demonstrate that NRF2 is a major target of p53-independent tumor suppression by ARF and also suggest that the ARF-NRF2 interaction acts as a new checkpoint for oxidative stress responses. Chen et al., identified ARF as a key regulator of NRF2-mediated activation of SLC7A11, a component of the cystine/glutamate antiporter that regulates reactive oxygen species (ROS)-induced ferroptosis. They showed that the ARF-NRF2 interaction is critical for p53-independent ferroptosis and tumor suppression induced by ARF.
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