Inhibition of Nek2 by small molecules affects proteasome activity

  • Biomed Res Int. 2014:2014:273180. doi: 10.1155/2014/273180.
Lingyao Meng  1 ,  Kent Carpenter  2 ,  Alexis Mollard  1 ,  Hariprasad Vankayalapati  1 ,  Steven L Warner  2 ,  Sunil Sharma  3 ,  Guido Tricot  4 ,  Fenghuang Zhan  4 ,  David J Bearss  2
Affiliations
  • 1. Center for Investigational Therapeutics, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
  • 2. Tolero Pharmaceuticals Inc., 2975 Executive Parkway, Suite 320, Lehi, UT 84043, USA.
  • 3. 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.
  • 4. Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA.
PMID: 25313354 DOI: 10.1155/2014/273180
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.

Materials and 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.

Conclusion: 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.

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