Metabolic targeting of oncogene MYC by selective activation of the proton-coupled monocarboxylate family of transporters
Metabolic targeting of oncogene MYC by selective activation of the proton-coupled monocarboxylate family of transporters
复制标题
通过选择性激活质子耦合单羧酸转运蛋白家族来代谢靶向癌基因 MYC
DOI：
10.1038/onc.2015.360
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发表时间：
2016-06-09
期刊：
影响因子：
8
通讯作者：
Qing, G.
中科院分区：
文献类型：
--
作者：
Gan, L.;Xiu, R.;Qing, G.
解除对MYC癌基因的调控会产生Myc蛋白，该蛋白调节癌细胞新陈代谢的多个方面，有助于获得癌细胞生长和增殖所必需的构件。因此，禁用Myc功能代表了癌症治疗的一个有吸引力的治疗选择。然而，能够直接针对Myc的药理学策略仍然难以捉摸。在此，我们确定了3-溴丙酮酸(3-BrPA)，一种主要抑制糖酵解的候选药物，在体内外优先诱导高表达MYC癌基因的人癌细胞大量死亡，而对那些表现出低MYC水平的癌细胞没有明显的影响。重要的是，对谷氨酰胺代谢的药理抑制协同增强了3-BrPA对MYC的合成致死靶向，部分原因是这种结合引起了代谢障碍。从机制上讲，我们发现使癌细胞有效摄取3-BrPA的质子偶联单羧酸转运体1(MCT1)和MCT2被Myc选择性地激活。其中涉及两种调控机制：第一，Myc通过与MCT1和MCT2基因的特定识别位点结合，直接激活MCT1和MCT2的转录；第二，Myc转录抑制miR29a和miR29c，导致其靶蛋白MCT1表达增强。值得注意的是，在MYCN扩增的神经母细胞瘤和C-MYC过表达的淋巴瘤中，MCT1和MCT2的表达均显著高于无MYC过表达的肿瘤，这与预后不良和患者预后不良有关。这些结果确定了Myc使细胞对代谢抑制剂敏感的新机制，并验证了3-BrPA作为潜在的Myc选择性癌症治疗药物的有效性。
Deregulation of the MYC oncogene produces Myc protein that regulates multiple aspects of cancer cell metabolism, contributing to the acquisition of building blocks essential for cancer cell growth and proliferation. Therefore, disabling Myc function represents an attractive therapeutic option for cancer treatment. However, pharmacological strategies capable of directly targeting Myc remain elusive. Here, we identified that 3-bromopyruvate (3-BrPA), a drug candidate that primarily inhibits glycolysis, preferentially induced massive cell death in human cancer cells overexpressing the MYC oncogene, in vitro and in vivo, without appreciable effects on those exhibiting low MYC levels. Importantly, pharmacological inhibition of glutamine metabolism synergistically potentiated the synthetic lethal targeting of MYC by 3-BrPA due in part to the metabolic disturbance caused by this combination. Mechanistically, we identified that the proton-coupled monocarboxylate transporter 1 (MCT1) and MCT2, which enable efficient 3-BrPA uptake by cancer cells, were selectively activated by Myc. Two regulatory mechanisms were involved: first, Myc directly activated MCT1 and MCT2 transcription by binding to specific recognition sites of both genes; second, Myc transcriptionally repressed miR29a and miR29c, resulting in enhanced expression of their target protein MCT1. Of note, expressions of MCT1 and MCT2 were each significantly elevated in MYCN-amplified neuroblastomas and C-MYC-overexpressing lymphomas than in tumors without MYC overexpression, correlating with poor prognosis and unfavorable patient survival. These results identify a novel mechanism by which Myc sensitizes cells to metabolic inhibitors and validate 3-BrPA as potential Myc-selective cancer therapeutics.