LXR agonists inhibit LDL receptor upregulation, promote cholesterol efflux transporter
FRIDAY, Sept. 16 (HealthDay News) -- Liver X receptor (LXR) agonists cause inducible degrader of low-density lipoprotein receptor (LDLR)(IDOL)-mediated LDLR degradation and elevated expression of the ABCA1 cholesterol efflux transporter, which promotes cell death in a glioblastoma model, according to an experimental study published online Sept. 15 in Cancer Discovery.
Deliang Guo, Ph.D., from the Ohio State University Medical School in Columbus, and colleagues explored the role of cholesterol metabolism in glioblastoma pathogenesis, its association with epidermal growth factor receptor (EGFR)/phosphoinositide 3-kinase (PI3K) signaling, and its possible therapeutic application. Studies were conducted on glioblastoma cell lines, xenograft models, and clinical samples, including those from patients treated with lapatinib, an EGFR tyrosine kinase inhibitor.
The investigators identified an EGFR mutation (EGFRvIII)-activated, PI3K/sterol regulatory element-binding protein 1 (SREBP-1)-dependent tumor survival pathway through the LDLR. The LXR agonist GW3965 targeted LDLR, resulting in IDOL-mediated LDLR degradation and raised expression of the ABCA1 cholesterol efflux transporter. These mechanisms promoted tumor cell death in an in vivo glioblastoma model.
"This study reveals that glioblastoma 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," the authors write.
One of the study authors disclosed financial ties to the pharmaceutical and biopharmaceutical industries.
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