Cynthia Hong

Cellular cholesterol levels reflect a balance between uptake, efflux, and endogenous synthesis. Here we show that the sterol-responsive nuclear liver X receptor (LXR) helps maintain cholesterol homeostasis, not only through promotion of cholesterol efflux but also through suppression of low-density lipoprotein (LDL) uptake. LXR inhibits the LDL receptor (LDLR) pathway through transcriptional induction of Idol (inducible degrader of the LDLR), an E3 ubiquitin ligase that triggers ubiquitination of the LDLR on its cytoplasmic domain, thereby targeting it for degradation. LXR ligand reduces, whereas LXR knockout increases, LDLR protein levels in vivo in a tissue-selective manner. Idol knockdown in hepatocytes increases LDLR protein levels and promotes LDL uptake. Conversely, adenovirus-mediated expression of Idol in mouse liver promotes LDLR degradation and elevates plasma LDL levels. The LXR-Idol-LDLR axis defines a complementary pathway to sterol response element-binding proteins for sterol regulation of cholesterol uptake.

Abstract Glioblastoma (GBM) is the most common malignant primary brain tumor of adults and one of the most lethal of all cancers. Epidermal growth factor receptor (EGFR) mutations (EGFRvIII) and phosphoinositide 3-kinase (PI3K) hyperactivation are common in GBM, promoting tumor growth and survival, including through sterol regulatory element-binding protein 1 (SREBP-1)–dependent lipogenesis. The role of cholesterol metabolism in GBM pathogenesis, its association with EGFR/PI3K signaling, and its potential therapeutic targetability are unknown. In our investigation, studies of GBM cell lines, xenograft models, and GBM clinical samples, including those from patients treated with the EGFR tyrosine kinase inhibitor lapatinib, uncovered an EGFRvIII-activated, PI3K/SREBP-1–dependent tumor survival pathway through the low-density lipoprotein receptor (LDLR). Targeting LDLR with the liver X receptor (LXR) agonist GW3965 caused inducible degrader of LDLR (IDOL)–mediated LDLR degradation and increased expression of the ABCA1 cholesterol efflux transporter, potently promoting tumor cell death in an in vivo GBM model. These results show that EGFRvIII can promote tumor survival through PI3K/SREBP-1–dependent upregulation of LDLR and suggest a role for LXR agonists in the treatment of GBM patients. Significance: This study reveals that GBM cells have devised a mechanism to subvert the normal pathways for feedback inhibition of cholesterol homeostasis via EGFRvIII and PI3K-dependent activation of SREBP-1. We show that an LXR agonist causes IDOL-mediated LDLR degradation and increases expression of the ABCA1 cholesterol efflux transporter, potently promoting GBM cell death in vivo. These results suggest a role for LXR agonists in the treatment of GBM patients. Cancer Discovery; 1(5): 442–56. ©2011 AACR. Read the Commentary on this article by Moschetta, p. 381 This article is highlighted in the In This Issue feature, p. 367

ConspectusThe field of supramolecular chemistry has its foundation in molecular recognition and selective binding of guest molecules, often with remarkably strong binding affinities. The field evolved to leverage these favorable interactions between the host and its guest to catalyze simple, often biomimetic transformations. Drawing inspiration from these early studies, self-assembled supramolecular hosts continue to capture a significant amount of interest toward their development as catalysts for increasingly complex transformations. Nature often relies on microenvironments, derived from complex tertiary structures and a well-defined active site, to promote reactions with remarkable rate acceleration, substrate specificity, and product selectivity. Similarly, supramolecular chemists have become increasingly intrigued by the prospect that self-assembly of molecular components might generate defined and spatially segregated microenvironments that can catalyze complex transformations.Among the growing palette of supramolecular catalysts, an anionic, water-soluble, tetrahedral metal–ligand coordination host has found a range of applications in catalysis and beyond. Early work focused on characterizing and understanding this host and its various host–guest phenomena, which paved the path for exploiting these features to selectively promote desirable chemistries, including cyclizations, rearrangements, and bimolecular reactions. Although this early work matured into achievements of catalysis with dramatic rate accelerations as well as enantioenrichment, the afforded products were typically identical to those produced by background reactions that occurred outside of the host microenvironment.This Account describes our recent developments in the application of these anionic tetrahedral hosts as catalysts for organic and organometallic transformation. Inspiration from natural systems and unmet synthetic challenges led to supramolecular catalysis displaying unique divergences in reactivity to give products that are inaccessible from bulk solution. Additionally, these tetrahedral assemblies have been shown to catalyze a diverse range of transformations with notable rate acceleration over the uncatalyzed background reaction. The pursuit of complexity beyond supramolecular catalysis has since led to the integration of these tetrahedral catalysts in tandem with natural enzymes, as well as their application to dual catalysis to realize challenging synthetic reactions.Variation in the structure, including size and charge, of these tetrahedral catalysts has enabled recent studies that provide insights into connections between specific structural features of these hosts and their reactivities. These mechanistic studies reveal that the solvent exclusion properties, hydrophobic effects, confinement effects and electrostatic effects play important roles in the observed catalysis. Moreover, these features may be leveraged for the design of supramolecular catalysis beyond those described in this Account. Finally, the supramolecular chemistry detailed in this Account has presented the opportunity to emulate some of the mechanisms nature engages to achieve catalysis; however, this relationship need not be entirely unidirectional, as the examples describe herein can stand as simplified model systems for unravelling more complex biological processes.