The AMPK inhibitor Compound C is a potent AMPK-independent anti-glioma agent

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.

http://mct.aacrjournals.org/content/early/2014/01/11/1535-7163.MCT-13-0579.abstract

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