Dual regulation of energy metabolism by p53 in human cervix and breast cancer cells
Dual regulation of energy metabolism by p53 in human cervix and breast cancer cells
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DOI：
10.1016/j.bbamcr.2015.09.033
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发表时间：
2015-12-01
影响因子：
5.1
通讯作者：
Rodriguez-Enriquez, Sara
中科院分区：
文献类型：
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作者：
Hernandez-Resendiz, Ileana;Roman-Rosales, Alejandra;Rodriguez-Enriquez, Sara
在HeLa-L(p53蛋白表达水平可忽略不计的细胞)和HeLa-H(p53过表达细胞)中，分析了在常氧和低氧条件下，P53作为OXPhos和糖酵解调节剂的作用。在常氧条件下，HeLa-H与HeLa-L细胞相比，功能性P53、线粒体(酶含量)、线粒体电势(Delta Psi(M))和OxPhos通量增加，而糖酵解酶含量和糖酵解通量没有变化。OXPHOS为HeLa-H细胞提供了超过70%的ATP，抗线粒体药物抑制了细胞的增殖。在低氧条件下，两种细胞的增殖均受到抑制，但HeLa-H细胞的OxPhos蛋白含量、Delta Psi(M)和OxPhos通量显著降低。尽管与HeLa-L细胞相比，在低氧条件下糖酵解功能也减弱，但在HeLa-H细胞中，糖酵解提供了超过60%的细胞三磷酸腺苷。P53抑制剂倍氟菊酯-α作用后，HeLa-H细胞的能量代谢表型逆转为HeLa-L细胞的能量代谢表型。在常氧条件下，乳腺癌MCF7细胞的能量代谢表型与HeLa-H细胞相似，而p53shRNAMCF-7细胞的能量代谢表型与HeLa-L细胞相似。在低氧条件下，HeLa-H细胞自噬蛋白和溶酶体含量增加2-5倍，提示有丝分裂激活。这些结果表明，在常氧条件下，p53上调OxPhos的表达而不影响糖酵解，而在低氧条件下，p53同时下调OxPhos(严重)和糖酵解(微弱)。这些P53效应可能是通过形成P53-HIF-1α复合体来实现的。因此，P53对肿瘤能量代谢起着双重的、不同的调节作用，这取决于O-2水平。(C)2015爱思唯尔B.V.保留所有权利。
The role of p53 as modulator of OxPhos and glycolysis was analyzed in HeLa-L (cells containing negligible p53 protein levels) and HeLa-H (p53-overexpressing) human cervix cancer cells under normoxia and hypoxia. In normoxia, functional p53, mitochondria( enzyme contents, mitochondrial electrical potential (Delta Psi(m)) and OxPhos flux increased in HeLa-H vs. HeLa-L cells; whereas their glycolytic enzyme contents and glycolysis flux were unchanged. OxPhos provided more than 70% of the cellular ATP and proliferation was abolished by anti-mitochondrial drugs in HeLa-H cells. In hypoxia, both cell proliferations were suppressed, but HeLa-H cells exhibited a significant decrease in OxPhos protein contents, Delta Psi(m) and OxPhos flux. Although glycolytic function was also diminished vs. HeLa-L cells in hypoxia, glycolysis provided more than 60% of cellular ATP in HeLa-H cells. The energy metabolism phenotype of HeLa-H cells was reverted to that of HeLa-L cells by incubating with pifithrin-alpha, a p53-inhibitor. In normoxia, the energy metabolism phenotype of breast cancer MCF-7 cells was similar to that of HeLa-H cells, whereas p53shRNAMCF-7 cells resembled the HeLa-L cell phenotype. In hypoxia, autophagy proteins and lysosomes contents increased 2-5 times in HeLa-H cells suggesting mitophagy activation. These results indicated that under normoxia p53 up-regulated OxPhos without affecting glycolysis, whereas under hypoxia, p53 down-regulated both OxPhos (severely) and glycolysis (weakly). These p53 effects appeared mediated by the formation of p53-HIF-1 alpha complexes. Therefore, p53 exerts a dual and contrasting regulatory role on cancer energy metabolism, depending on the O-2 level. (C) 2015 Elsevier B.V. All rights reserved.