the anticancer plant triterpenoid, avicin d, regulates glucocorticoid receptor signaling implications for cellular metabolism抗癌植物三萜,avicin d,调节糖皮质激素受体信号对细胞代谢的影响.pdfVIP

The Anticancer Plant Triterpenoid, Avicin D, Regulates Glucocorticoid Receptor Signaling: Implications for Cellular Metabolism 1 1¤ 2 1 3 1 Valsala Haridas *, Zhi-Xiang Xu , Doug Kitchen , Anna Jiang , Peter Michels , Jordan U. Gutterman 1 Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America, 2 Department of Computer-Aided Drug Discovery, Albany Molecular Research, Inc., Albany, New York, United States of America, 3 Department of Metabolism and Biotransformations, Albany Molecular Research, Inc., Albany, New York, United States of America Abstract Avicins, a family of apoptotic triterpene electrophiles, are known to regulate cellular metabolism and energy homeostasis, by targeting the mitochondria. Having evolved from ‘‘ancient hopanoids,’’ avicins bear a structural resemblance with glucocorticoids (GCs), which are the endogenous regulators of metabolism and energy balance. These structural and functional similarities prompted us to compare the mode of action of avicin D with dexamethasone (Dex), a prototypical GC. Using cold competition assay, we show that Avicin D competes with Dex for binding to the GC receptor (GR), leading to its nuclear translocation. In contrast to Dex, avicin-induced nuclear translocation of GR does not result in transcriptional activation of GC-dependent genes. Instead we observe a decrease in the expression of GC-dependent metabolic proteins such as PEPCK and FASN. However, like Dex, avicin D treatment does induce a transrepressive effect on the pro- inflammatory transcription factor NF-kB. While avicin’s ability to inhibit NF-kB and its downstream t