The AMPK inhibitor compound C is a potent AMPK-independent antiglioma agent.
The AMPK inhibitor compound C is a potent AMPK-independent antiglioma agent.
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DOI：
10.1158/1535-7163.mct-13-0579
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发表时间：
2014-03
影响因子：
5.7
通讯作者：
Dasgupta B
中科院分区：
文献类型：
--
作者：
Liu X;Chhipa RR;Nakano I;Dasgupta B
AMPK是一种进化上保守的能量感受器，对细胞的生长、增殖、存活和代谢调节非常重要。活性AMPK抑制生物合成酶，如mTOR和乙酰辅酶A羧基酶(分别是蛋白质和脂肪合成所必需的)，以确保细胞在代谢危机期间保持必要的营养和能量。尽管我们知道这个极其重要的激酶，但还没有特定的化学抑制剂来检查它的功能。然而，一种被称为化合物C的小分子(也称为多索吗啡)已被广泛用于基于细胞的、生化的和体内的检测中，作为一种选择性的AMPK抑制剂。在几乎所有这些报告中，包括最近对胶质瘤的一项研究，化合物C的生化和细胞效应都被归因于它对AMPK的抑制作用。在检测人脑胶质瘤中AMPK的激活状态时，我们观察到胶质母细胞瘤(GbM)表达大量的活性AMPK。化合物C通过抑制细胞增殖和诱导细胞死亡，有效地降低了胶质瘤的体外活性。正如预期的那样，化合物C抑制AMPK；然而，该化合物的所有抗增殖作用都不依赖于AMPK。相反，化合物C通过多种机制杀死胶质瘤细胞，包括激活Calain/Cathepsin途径，抑制AKT，mTORC1/C2，细胞周期阻滞在G2M，诱导坏死下垂和自噬。重要的是，正常星形胶质细胞对化合物C的敏感性显著降低。综上所述，化合物C是一种非常有效的抗胶质瘤药物，但我们建议，当该化合物被用作AMPK抑制剂时，在解释结果时应谨慎。
AMPK is an evolutionarily conserved energy sensor important for cell growth, proliferation, survival and metabolic regulation. Active AMPK inhibits biosynthetic enzymes like mTOR and acetyl CoA carboxylase (required for protein and lipid synthesis, respectively) to ensure that cells maintain essential nutrients and energy during metabolic crisis. Despite our knowledge about this incredibly important kinase, no specific chemical inhibitors are available to examine its function. However, one small molecule known as Compound C (also called dorsomorphin) has been widely used in cell-based, biochemical and in vivo assays as a selective AMPK inhibitor. In nearly all these reports including a recent study in glioma, the biochemical and cellular effects of Compound C has been attributed to its inhibitory action towards AMPK. While examining the status of AMPK activation in human gliomas, we observed that glioblastomas (GBMs) express copious amount of active AMPK. Compound C effectively reduced glioma viability in vitro both by inhibiting proliferation and inducing cell death. As expected, Compound C inhibited AMPK; however, all the antiproliferative effects of this compound were AMPK-independent. Instead, Compound C killed glioma cells by multiple mechanisms including activation of the Calpain/Cathepsin pathway, inhibition of AKT, mTORC1/C2, cell cycle block at G2M and induction of necroptosis and autophagy. Importantly, normal astrocytes were significantly less susceptible to Compound C. In summary, Compound C is an extremely potent anti-glioma agent but we suggest that caution should be taken in interpreting results when this compound is used as an AMPK inhibitor.