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Activation of liver X receptors inhibits hedgehog signaling, clonogenic growth, and self-renewal in multiple myeloma.
- Source :
-
Molecular cancer therapeutics [Mol Cancer Ther] 2014 Jul; Vol. 13 (7), pp. 1873-81. Date of Electronic Publication: 2014 May 07. - Publication Year :
- 2014
-
Abstract
- The Hedgehog (Hh) signaling pathway is aberrantly activated in a wide variety of human cancers, and recent clinical studies have demonstrated that pathway inhibitors are effective in advanced basal cell carcinoma (BCC). The majority of these agents have been designed to target SMOOTHENED (SMO), a transmembrane regulator of Hh signaling, but subsequent mutations in SMO have been found to generate drug resistance. In other cancers, oncogenic events that bypass SMO may activate canonical Hh signaling, and SMO antagonists have not demonstrated significant activity in several diseases. Therefore, alternative strategies targeting the Hh pathway downstream of SMO may have clinical utility. Liver X receptors (LXR) regulate cholesterol and fatty acid homeostasis, and LXR activation can inhibit the Hh pathway in normal mouse embryonic fibroblasts. We examined the effects of LXR activation on Hh signaling in human multiple myeloma cells and found that LXR agonists inhibited Hh pathway activity and clonogenic tumor growth in vitro. LXR activation also inhibited putative multiple myeloma cancer stem cells in vivo leading to the loss of tumor initiating and self-renewal potential. Finally, Hh signaling was inhibited downstream of SMO, suggesting that LXR agonists may represent a novel strategy to target pathogenic Hh signaling as well as treat multiple myeloma.<br /> (©2014 American Association for Cancer Research.)
- Subjects :
- Animals
Cell Line, Tumor
Cell Proliferation physiology
Cell Survival physiology
Clone Cells
Humans
Liver X Receptors
Mice
Mice, Inbred NOD
Multiple Myeloma genetics
Multiple Myeloma pathology
Orphan Nuclear Receptors genetics
Orphan Nuclear Receptors metabolism
Signal Transduction drug effects
Transfection
Hedgehog Proteins antagonists & inhibitors
Hydrocarbons, Fluorinated pharmacology
Multiple Myeloma drug therapy
Multiple Myeloma metabolism
Orphan Nuclear Receptors agonists
Sulfonamides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1538-8514
- Volume :
- 13
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Molecular cancer therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 24807964
- Full Text :
- https://doi.org/10.1158/1535-7163.MCT-13-0997