The environmental carcinogen benzo[a]pyrene induces a Warburg-like metabolic reprogramming dependent on NHE1 and associated with cell survival.
The environmental carcinogen benzo[a]pyrene induces a Warburg-like metabolic reprogramming dependent on NHE1 and associated with cell survival.
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DOI：
10.1038/srep30776
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发表时间：
2016-08-04
影响因子：
4.6
通讯作者：
Lagadic-Gossmann D
中科院分区：
文献类型：
--
作者：
Hardonnière K;Saunier E;Lemarié A;Fernier M;Gallais I;Héliès-Toussaint C;Mograbi B;Antonio S;Bénit P;Rustin P;Janin M;Habarou F;Ottolenghi C;Lavault MT;Benelli C;Sergent O;Huc L;Bortoli S;Lagadic-Gossmann D
癌细胞在许多细胞过程中表现出改变。癌症的一个核心标志是瓦伯格效应，这是一种糖酵解重编程，可以使细胞存活和增殖。尽管环境污染物对癌症发展的贡献已被广泛接受，但其潜在机制仍需澄清。苯并[a]芘（B[a]P）是多环芳烃的原型，具有遗传毒性和致癌作用，根据国际癌症研究机构的数据，它是人类致癌物。除了触发细胞凋亡信号外，B[a]P 还可能诱导生存信号，这两种信号都可能参与癌症的促进。我们之前提出，B[a]P 诱导的线粒体功能障碍，尤其是膜超极化，可能会触发大鼠肝上皮 F258 细胞中的细胞生存信号传导。在这里，我们通过关注能量代谢进一步表征这些功能障碍。我们发现 B[a]P 促进代谢重编程。细胞呼吸减少，乳酸产量增加。这些变化与三羧酸循环的改变有关，这可能涉及线粒体复合物 II 的功能障碍。糖酵解转变依赖于 Na+/H+ 交换器 1 (NHE1) 的激活，并且似乎是 B[a]P 诱导的与细胞表型变化（上皮间质转化和细胞迁移）相关的细胞存活的关键特征。
Cancer cells display alterations in many cellular processes. One core hallmark of cancer is the Warburg effect which is a glycolytic reprogramming that allows cells to survive and proliferate. Although the contributions of environmental contaminants to cancer development are widely accepted, the underlying mechanisms have to be clarified. Benzo[a]pyrene (B[a]P), the prototype of polycyclic aromatic hydrocarbons, exhibits genotoxic and carcinogenic effects, and it is a human carcinogen according to the International Agency for Research on Cancer. In addition to triggering apoptotic signals, B[a]P may induce survival signals, both of which are likely to be involved in cancer promotion. We previously suggested that B[a]P-induced mitochondrial dysfunctions, especially membrane hyperpolarization, might trigger cell survival signaling in rat hepatic epithelial F258 cells. Here, we further characterized these dysfunctions by focusing on energy metabolism. We found that B[a]P promoted a metabolic reprogramming. Cell respiration decreased and lactate production increased. These changes were associated with alterations in the tricarboxylic acid cycle which likely involve a dysfunction of the mitochondrial complex II. The glycolytic shift relied on activation of the Na+/H+ exchanger 1 (NHE1) and appeared to be a key feature in B[a]P-induced cell survival related to changes in cell phenotype (epithelial-to-mesenchymal transition and cell migration).