title: Aurora and IKK kinases cooperatively interact to protect multiple myeloma cells from Apo2L/TRAIL.
abstract: Constitutive activation of the canonical and noncanonical nuclear factor-κB (NF-κB) pathways is frequent in multiple myeloma (MM) and can compromise sensitivity to TRAIL. In this study, we demonstrate that Aurora kinases physically and functionally interact with the key regulators of canonical and noncanonical NF-κB pathways IκB kinase β (IKKβ) and IKKα to activate NF-κB in MM, and the pharmacological blockade of Aurora kinase activity induces TRAIL sensitization in MM because it abrogates TRAIL-induced activation of NF-κB. We specifically found that TRAIL induces prosurvival signaling by increasing the phosphorylation state of both Aurora and IKK kinases and their physical interactions, and the blockade of Aurora kinase activity by pan-Aurora kinase inhibitors (pan-AKIs) disrupts TRAIL-induced survival signaling by effectively reducing Aurora-IKK kinase interactions and NF-κB activation. Pan-AKIs consistently blocked TRAIL induction of the antiapoptotic NF-κB target genes A1/Bfl-1 and/or Mcl-1, both important targets for TRAIL sensitization in MM cells. In summary, these results identify a novel interaction between Aurora and IKK kinases and show that these pathways can cooperate to promote TRAIL resistance. Finally, combining pan-AKIs with TRAIL in vivo showed dramatic efficacy in a multidrug-resistant human myeloma xenograft model. These findings suggest that combining Aurora kinase inhibitors with TRAIL may have therapeutic benefit in MM.
authors: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy;
authors: Laura
authors: L
authors: Mazzera
authors: Guerino
authors: G
authors: Lombardi
authors: Manuela
authors: M
authors: Abeltino
authors: Micaela
authors: M
authors: Ricca
authors: Gaetano
authors: G
authors: Donofrio
authors: Nicola
authors: N
authors: Giuliani
authors: Anna Maria
authors: AM
authors: Cantoni
authors: Attilio
authors: A
authors: Corradi
authors: Antonio
authors: A
authors: Bonati
authors: Paolo
authors: P
authors: Lunghi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009101:Multiple Myeloma / Q000201:enzymology* / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D003521:Cyclopropanes; D011743:Pyrimidines
chemical_list: D064096:Aurora Kinase A; D051550:I-kappa B Kinase; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011758:Pyrroles; D053221:TNF-Related Apoptosis-Inducing Ligand; C524543:PHA 680632; C505653:TNFSF10 protein, human; C484810:tozasertib; D003521:Cyclopropanes; D011743:Pyrimidines; C576917:AURKA protein, human; C496560:IKBKB protein, human