title: The unfolded protein response selectively targets active smoothened mutants.
abstract: The Hedgehog signaling pathway, an essential regulator of developmental patterning, has been implicated in playing causative and survival roles in a range of human cancers. The signal-transducing component of the pathway, Smoothened, has revealed itself to be an efficacious therapeutic target in combating oncogenic signaling. However, therapeutic challenges remain in cases where tumors acquire resistance to Smoothened antagonists, and also in cases where signaling is driven by active Smoothened mutants that exhibit reduced sensitivity to these compounds. We previously demonstrated that active Smoothened mutants are subjected to prolonged endoplasmic reticulum (ER) retention, likely due to their mutations triggering conformation shifts that are detected by ER quality control. We attempted to exploit this biology and demonstrate that deregulated Hedgehog signaling driven by active Smoothened mutants is specifically attenuated by ER stressors that induce the unfolded protein response (UPR). Upon UPR induction, active Smoothened mutants are targeted by ER-associated degradation, resulting in attenuation of inappropriate pathway activity. Accordingly, we found that the UPR agonist thapsigargin attenuated mutant Smoothened-induced phenotypes in vivo in Drosophila melanogaster. Wild-type Smoothened and physiological Hedgehog patterning were not affected, suggesting that UPR modulation may provide a novel therapeutic window to be evaluated for targeting active Smoothened mutants in disease.
authors.affiliation: Department of Biochemistry, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA.
authors.forename: Suresh
authors.initials: S
authors.lastname: Marada
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Stewart
authors.forename: William J
authors.initials: WJ
authors.lastname: Bodeen
authors.forename: Young-Goo
authors.initials: YG
authors.lastname: Han
authors.forename: Stacey K
authors.initials: SK
authors.lastname: Ogden
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D002280:Basal Cell Carcinoma / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000502:physiology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D053823:Hedgehog Proteins / Q000378:metabolism*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008527:Medulloblastoma / Q000378:metabolism; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D000072086:Smoothened Receptor; D019284:Thapsigargin / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D001897:Boronic Acids; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D053823:Hedgehog Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D047029:Lactams, Macrocyclic; D050505:Mutant Proteins; D011719:Pyrazines; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; C534922:SNX 2112; D000072086:Smoothened Receptor; C517798:Xbp1 protein, Drosophila; C100664:smo protein, Drosophila; D049452:Green Fluorescent Proteins; C112765:tanespimycin; D019284:Thapsigargin; D000069286:Bortezomib; D044767:Ubiquitin-Protein Ligases