title: The anticancer plant triterpenoid, avicin D, regulates glucocorticoid receptor signaling: implications for cellular metabolism.
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-κB. While avicin's ability to inhibit NF-κB and its downstream targets appear to be GR-dependent, its pro-apoptotic effects were independent of GR expression. Using various deletion mutants of GR, we demonstrate the requirement of both the DNA and ligand binding domains of GR in mediating avicin D's transrepressive effects. Modeling of avicin-GR interaction revealed that avicin molecule binds only to the antagonist confirmation of GR. These findings suggest that avicin D has properties of being a selective GR modulator that separates transactivation from transrepression. Since the gene-activating properties of GR are mainly linked to its metabolic effects, and the negative interference with the activity of transcription factors to its anti-inflammatory and immune suppressive effects, the identification of such a dissociated GR ligand could have great potential for therapeutic use.
authors: Department of Systems Biology, University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America. vharidas@mdanderson.org
authors: Valsala
authors: V
authors: Haridas
authors: Zhi-Xiang
authors: ZX
authors: Xu
authors: Doug
authors: D
authors: Kitchen
authors: Anna
authors: A
authors: Jiang
authors: Peter
authors: P
authors: Michels
authors: Jordan U
authors: JU
authors: Gutterman
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002477:Cells / Q000187:drug effects / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D054890:Fatty Acid Synthase, Type I / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008954:Models, Biological; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D012503:Saponins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects; D014315:Triterpenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D012503:Saponins; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; C478445:avicin D; D004247:DNA; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D010729:Phosphoenolpyruvate Carboxykinase (GTP)