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首页> 外文期刊>The EMBO journal. >Targeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival
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Targeting the Warburg effect via LDHA inhibition engages ATF4 signaling for cancer cell survival

机译：针对通过LDHA抑制Warburg效应从事ATF4信号对癌细胞的生存

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摘要

Nutrient restriction reprograms cellular signaling and metabolic network to shape cancer phenotype. Lactate dehydrogenase A (LDHA) has a key role in aerobic glycolysis (the Warburg effect) through regeneration of the electron acceptor NAD+?and is widely regarded as a desirable target for cancer therapeutics. However, the mechanisms of cellular response and adaptation to LDHA inhibition remain largely unknown. Here, we show that LDHA activity supports serine and aspartate biosynthesis. Surprisingly, however, LDHA inhibition fails to impact human melanoma cell proliferation, survival, or tumor growth. Reduced intracellular serine and aspartate following LDHA inhibition engage GCN2‐ATF4 signaling to initiate an expansive pro‐survival response. This includes the upregulation of glutamine transporter SLC1A5 and glutamine uptake, with concomitant build‐up of essential amino acids, and mTORC1 activation, to ameliorate the effects of LDHA inhibition. Tumors with low LDHA expression and melanoma patients acquiring resistance to MAPK signaling inhibitors, which target the Warburg effect, exhibit altered metabolic gene expression reminiscent of the ATF4‐mediated survival signaling. ATF4‐controlled survival mechanisms conferring synthetic vulnerability to the approaches targeting the Warburg effect offer efficacious therapeutic strategies.
机译：营养限制重组细胞信号和代谢网络形状癌症表型。乳酸脱氢酶(LDHA)具有关键作用有氧糖酵解(Warburg效应)再生的电子受体NAD + ?广泛认为是癌症的一个理想的目标疗法。响应和适应LDHA抑制依然存在很大程度上是未知的。支持丝氨酸和天冬氨酸生物合成。令人惊讶的是,然而,LDHA抑制失败影响人类黑色素瘤细胞增殖,生存,或肿瘤的生长。丝氨酸和天冬氨酸LDHA抑制参与GCN2 ATF4信号来启动一个广阔的职业生存的反应。谷氨酰胺转运体的upregulation SLC1A5和谷氨酰胺吸收,同时建立起来必需氨基酸,mTORC1激活,改善LDHA抑制的影响。较低的肿瘤LDHA表达式和黑色素瘤病人获得抵抗MAPK信号抑制剂,目标Warburg效应,展览改变代谢基因表达让人想起ATF4介导应承担的生存信号。赋予合成漏洞的方法针对Warburg效应有效的治疗策略。

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