PHD2 Targeting Overcomes Breast Cancer Cell Death upon Glucose Starvation in a PP2A/B55α-Mediated Manner.
PHD2 Targeting Overcomes Breast Cancer Cell Death upon Glucose Starvation in a PP2A/B55α-Mediated Manner.
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DOI：
10.1016/j.celrep.2017.02.081
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发表时间：
2017-03-21
期刊：
影响因子：
8.8
通讯作者：
Mazzone M
中科院分区：
文献类型：
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作者：
Di Conza G;Trusso Cafarello S;Zheng X;Zhang Q;Mazzone M
B55α是PP 2A磷酸酶的调节亚基。我们最近发现，B55α相关的PP 2A促进HIF-脯氨酰羟化酶PHD 2的部分失活。在这里，我们表明，反过来，PHD 2通过在脯氨酸319处羟基化B55α来触发B55α的降解。在葡萄糖饥饿的情况下，PHD 2降低了B55α蛋白水平，这与MDA-MB 231和MCF 7乳腺癌细胞死亡相关。在这些条件下，PHD 2沉默拯救了B55α降解，克服了细胞凋亡，而在对葡萄糖饥饿具有抗性的SKBR 3乳腺癌细胞中，B55α敲低恢复了细胞死亡并防止了体外肿瘤生长。用葡萄糖竞争剂2-脱氧葡萄糖处理MDA-MB 231来源的异种移植物导致在PHD 2存在下的肿瘤消退。PHD 2的敲低通过阻止细胞凋亡诱导B55α积累和治疗抗性。总的来说，我们的数据揭示了B55α作为PHD 2底物的作用，并强调了PHD 2-B55α在营养剥夺反应中的作用。PHD 2羟基化和降解B55α，PP 2A磷酸酶的调节亚基在没有葡萄糖的情况下，高α KG与富马酸盐的比例有利于PHD 2活化。在葡萄糖饥饿的情况下，活性PHD 2降解B55 α并促进细胞死亡。表明，在葡萄糖饥饿后，高α KG与富马酸盐的比例有利于PHD 2活化，通过降解B55α促进细胞凋亡。在乳腺癌细胞中，PHD 2敲低阻止B55α降解并克服响应葡萄糖饥饿的凋亡。PHD 2沉默的MDA-MB 231异种移植物显示B55α的蓄积和对2DG治疗的抗性。
B55α is a regulatory subunit of the PP2A phosphatase. We have recently found that B55α-associated PP2A promotes partial deactivation of the HIF-prolyl-hydroxylase enzyme PHD2. Here, we show that, in turn, PHD2 triggers degradation of B55α by hydroxylating it at proline 319. In the context of glucose starvation, PHD2 reduces B55α protein levels, which correlates with MDA-MB231 and MCF7 breast cancer cell death. Under these conditions, PHD2 silencing rescues B55α degradation, overcoming apoptosis, whereas in SKBR3 breast cancer cells showing resistance to glucose starvation, B55α knockdown restores cell death and prevents neoplastic growth in vitro. Treatment of MDA-MB231-derived xenografts with the glucose competitor 2-deoxy-glucose leads to tumor regression in the presence of PHD2. Knockdown of PHD2 induces B55α accumulation and treatment resistance by preventing cell apoptosis. Overall, our data unravel B55α as a PHD2 substrate and highlight a role for PHD2-B55α in the response to nutrient deprivation. PHD2 hydroxylates and degrades B55α, a regulatory subunit of PP2A phosphatase In the absence of glucose, a high αKG-to-fumarate ratio favors PHD2 activation Active PHD2 degrades B55α and promotes cell death under glucose starvation PHD2-silenced xenografts showed accumulation of B55α and resistance to 2DG treatment Di Conza et al. show that, following glucose starvation, a high αKG-to-fumarate ratio favors PHD2 activation that promotes apoptosis by degrading B55α. In breast cancer cells, PHD2 knockdown prevents B55α degradation and overcomes apoptosis in response to glucose starvation. PHD2-silenced MDA-MB231 xenografts show accumulation of B55α and resistance to 2DG treatment.