title: Canonical and noncanonical Hedgehog pathway in the pathogenesis of multiple myeloma.
abstract: The Hedgehog (Hh) pathway is required for cell-fate determination during the embryonic life, as well as cell growth and differentiation in the adult organism, where the inappropriate activation has been implicated in several cancers. Here we demonstrate that Hh signaling plays a significant role in growth and survival of multiple myeloma (MM) cells. We observed that CD138(+) MM cells express Hh genes and confirmed Smoothened (Smo)-dependent Hh signaling in MM using a novel synthetic Smo inhibitor, NVP-LDE225 (Novartis), which decreased MM cell viability by inducing specific down-regulation of Gli1 and Ptch1, hallmarks of Hh activity. In addition, we detected a nuclear localization of Gli1 in MM cells, which is completely abrogated by Forskolin, a Gli1-modulating compound, confirming Smo-independent mechanisms leading to Hh activation in MM. Finally, we identified that bone marrow stromal cells are a source of the Shh ligand, although they are resistant to the Hh inhibitor because of defective Smo expression and Ptch1 up-regulation. Further in vitro as well as in vivo studies showed antitumor efficacy of NVP-LDE225 in combination with bortezomib. Altogether, our data demonstrate activation of both canonical and noncanonical Hh pathway in MM, thus providing the rationale for testing Hh inhibitors in clinical trials to improve MM patient outcome.
authors: Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Simona
authors: S
authors: Blotta
authors: Jana
authors: J
authors: Jakubikova
authors: Teresa
authors: T
authors: Calimeri
authors: Aldo M
authors: AM
authors: Roccaro
authors: Nicola
authors: N
authors: Amodio
authors: Abdel Kareem
authors: AK
authors: Azab
authors: Umberto
authors: U
authors: Foresta
authors: Constantine S
authors: CS
authors: Mitsiades
authors: Marco
authors: M
authors: Rossi
authors: Katia
authors: K
authors: Todoerti
authors: Stefano
authors: S
authors: Molica
authors: Fortunato
authors: F
authors: Morabito
authors: Antonino
authors: A
authors: Neri
authors: Piersandro
authors: P
authors: Tagliaferri
authors: Pierfrancesco
authors: P
authors: Tassone
authors: Kenneth C
authors: KC
authors: Anderson
authors: Nikhil C
authors: NC
authors: Munshi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010950:Plasma Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor; D053668:Syndecan-1 / Q000032:analysis
chemical_list: D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D001897:Boronic Acids; D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011719:Pyrazines; D011725:Pyridines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D053668:Syndecan-1; C561435:sonidegib; D000069286:Bortezomib