title: Activation of liver X receptors inhibits hedgehog signaling, clonogenic growth, and self-renewal in multiple myeloma.
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.
authors.affiliation: Authors' Affiliations: Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Jasmin R
authors.initials: JR
authors.lastname: Agarwal
authors.affiliation: Authors' Affiliations: Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Qiuju
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Authors' Affiliations: Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Tanno
authors.affiliation: Authors' Affiliations: Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Zeshaan
authors.initials: Z
authors.lastname: Rasheed
authors.affiliation: Division of Hematology and Center for the Study of Blood Diseases, Norris Comprehensive Cancer Center, University of Southern California; and.
authors.forename: Akil
authors.initials: A
authors.lastname: Merchant
authors.affiliation: Authors' Affiliations: Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Nilanjan
authors.initials: N
authors.lastname: Ghosh
authors.affiliation: Authors' Affiliations: Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Ivan
authors.initials: I
authors.lastname: Borrello
authors.affiliation: Authors' Affiliations: Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland;
authors.forename: Carol Ann
authors.initials: CA
authors.lastname: Huff
authors.affiliation: Department of Medicine, University of California Los Angeles, Los Angeles, California.
authors.forename: Farhad
authors.initials: F
authors.lastname: Parhami
authors.affiliation: Authors' Affiliations: Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; matsuwi@jhmi.edu.
authors.forename: William
authors.initials: W
authors.lastname: Matsui
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002999:Clone Cells; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D000071518:Liver X Receptors; D051379:Mice; D016688:Mice, Inbred NOD; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D014162:Transfection; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D053823:Hedgehog Proteins; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides