title: Inhibition of Nek2 by small molecules affects proteasome activity.
abstract: BACKGROUND
  Nek2 is a serine/threonine kinase localized to the centrosome. It promotes cell cycle progression from G2 to M by inducing centrosome separation. Recent studies have shown that high Nek2 expression is correlated with drug resistance in multiple myeloma patients.
  
  
  METHODS
  To investigate the role of Nek2 in bortezomib resistance, we ectopically overexpressed Nek2 in several cancer cell lines, including multiple myeloma lines. Small-molecule inhibitors of Nek2 were discovered using an in-house library of compounds. We tested the inhibitors on proteasome and cell cycle activity in several cell lines.
  
  
  RESULTS
  Proteasome activity was elevated in Nek2-overexpressing cell lines. The Nek2 inhibitors inhibited proteasome activity in these cancer cell lines. Treatment with these inhibitors resulted in inhibition of proteasome-mediated degradation of several cell cycle regulators in HeLa cells, leaving them arrested in G2/M. Combining these Nek2 inhibitors with bortezomib increased the efficacy of bortezomib in decreasing proteasome activity in vitro. Treatment with these novel Nek2 inhibitors successfully mitigated drug resistance in bortezomib-resistant multiple myeloma.
  
  
  CONCLUSIONS
  Nek2 plays a central role in proteasome-mediated cell cycle regulation and in conferring resistance to bortezomib in cancer cells. Taken together, our results introduce Nek2 as a therapeutic target in bortezomib-resistant multiple myeloma.
authors.affiliation: Center for Investigational Therapeutics, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
authors.forename: Lingyao
authors.initials: L
authors.lastname: Meng
authors.affiliation: Tolero Pharmaceuticals Inc., 2975 Executive Parkway, Suite 320, Lehi, UT 84043, USA.
authors.forename: Kent
authors.identifier: 0000-0001-5098-1773
authors.initials: K
authors.lastname: Carpenter
authors.affiliation: Center for Investigational Therapeutics, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
authors.forename: Alexis
authors.identifier: 0000-0002-3289-4227
authors.initials: A
authors.lastname: Mollard
authors.affiliation: Center for Investigational Therapeutics, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
authors.forename: Hariprasad
authors.identifier: 0000-0002-5477-2124
authors.initials: H
authors.lastname: Vankayalapati
authors.affiliation: Tolero Pharmaceuticals Inc., 2975 Executive Parkway, Suite 320, Lehi, UT 84043, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Warner
authors.affiliation: Center for Investigational Therapeutics, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA ; Division of Medical Oncology, University of Utah, Salt Lake City, UT 84312, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Guido
authors.identifier: 0000-0002-3111-9739
authors.initials: G
authors.lastname: Tricot
authors.affiliation: Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Fenghuang
authors.initials: F
authors.lastname: Zhan
authors.affiliation: Tolero Pharmaceuticals Inc., 2975 Executive Parkway, Suite 320, Lehi, UT 84043, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Bearss
mesh_terms: D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D016203:CDC2 Protein Kinase / Q000378:metabolism; D045744:Cell Line, Tumor; D019926:Cyclin B / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D000072379:NIMA-Related Kinases; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001897:Boronic Acids; D019926:Cyclin B; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D054852:Small Molecule Libraries; D000069286:Bortezomib; C089441:NEK2 protein, human; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D046988:Proteasome Endopeptidase Complex