American Association for Cancer Research
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Supplementary Figures 1 - 4 from The AMPK Inhibitor Compound C Is a Potent AMPK-Independent Antiglioma Agent

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posted on 2023-04-03, 14:07 authored by Xiaona Liu, Rishi Raj Chhipa, Ichiro Nakano, Biplab Dasgupta

PDF file - 589K, Figure S1. Antiproliferative effects of Compound C in glioma cells. Figure S2. Compound C induces AMPK-independent autophagy and the antiproliferative effects of Compound C are not blocked by autophagy and apoptosis inhibitors. Figure S3. Constitutively active Akt fails to block Compound C?s antiproliferative action. Figure S4. Effects of Compound C on glioma cell cycle.

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ARTICLE ABSTRACT

AMP-activated protein kinase (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 have been attributed to its inhibitory action toward AMPK. While examining the status of AMPK activation in human gliomas, we observed that glioblastomas 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 G2–M, and induction of necroptosis and autophagy. Importantly, normal astrocytes were significantly less susceptible to compound C. In summary, compound C is an extremely potent antiglioma agent but we suggest that caution should be taken in interpreting results when this compound is used as an AMPK inhibitor. Mol Cancer Ther; 13(3); 596–605. ©2014 AACR.