title: Proteasome inhibition reverses hedgehog inhibitor and taxane resistance in ovarian cancer.
abstract: The goal of this study was to determine whether combined targeted therapies, specifically those against the Notch, hedgehog and ubiquitin-proteasome pathways, could overcome ovarian cancer chemoresistance. Chemoresistant ovarian cancer cells were exposed to gamma-secretase inhibitors (GSI-I, Compound E) or the proteasome inhibitor bortezomib, alone and in combination with the hedgehog antagonist, LDE225. Bortezomib, alone and in combination with LDE225, was evaluated for effects on paclitaxel efficacy. Cell viability and cell cycle analysis were assessed by MTT assay and propidium iodide staining, respectively. Proteasome activity and gene expression were determined by luminescence assay and qPCR, respectively. Studies demonstrated that GSI-I, but not Compound E, inhibited proteasome activity, similar to bortezomib. Proteasome inhibition decreased hedgehog target genes (PTCH1, GLI1 and GLI2) and increased LDE225 sensitivity in vitro. Bortezomib, alone and in combination with LDE225, increased paclitaxel sensitivity through apoptosis and G2/M arrest. Expression of the multi-drug resistance gene ABCB1/MDR1 was decreased and acetylation of α-tubulin, a marker of microtubule stabilization, was increased following bortezomib treatment. HDAC6 inhibitor tubastatin-a demonstrated that microtubule effects are associated with hedgehog inhibition and sensitization to paclitaxel and LDE225. These results suggest that proteasome inhibition, through alteration of microtubule dynamics and hedgehog signaling, can reverse taxane-mediated chemoresistance.
authors.affiliation: Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL. McWhorter School of Pharmacy, Samford University, Birmingham, AL. These authors contributed equally to this work.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Steg
authors.affiliation: Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL. These authors contributed equally to this work.
authors.forename: Mata R
authors.initials: MR
authors.lastname: Burke
authors.affiliation: Institute of Oral Health Research, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Hope M
authors.initials: HM
authors.lastname: Amm
authors.affiliation: Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Ashwini A
authors.initials: AA
authors.lastname: Katre
authors.affiliation: Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Dobbin
authors.affiliation: Department of Obstetrics and Gynecology Busan Paik Hospital, Inje University, Gimhae, South Korea.
authors.forename: Dae Hoon
authors.initials: DH
authors.lastname: Jeong
authors.affiliation: Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA. These authors contributed equally to this work.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Landen
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000069286:Bortezomib; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction; D043823:Taxoids / Q000494:pharmacology*
chemical_list: D001713:Biphenyl Compounds; D001897:Boronic Acids; D001952:Bridged-Ring Compounds; D053823:Hedgehog Proteins; D061988:Proteasome Inhibitors; D011719:Pyrazines; D011725:Pyridines; D043823:Taxoids; C561435:sonidegib; C080625:taxane; D000069286:Bortezomib