We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Inhibition of Nek2 by Small Molecules Affects Proteasome Activity.
- Authors
Lingyao Meng; Carpenter, Kent; Mollard, Alexis; Vankayalapati, Hariprasad; Warner, Steven L.; Sharma, Sunil; Tricot, Guido; Fenghuang Zhan; Bearss, David J.
- 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 highNek2 expression is correlatedwith drug resistance inmultiple myeloma patients. Materials and Methods. To investigate the role of Nek2 in bortezomib resistance, we ectopically overexpressed Nek2 in several cancer cell lines, includingmultiplemyeloma lines. Small-molecule inhibitors of Nek2 were discovered using an inhouse 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 introduceNek2 as a therapeutic target in bortezomibresistant multiple myeloma.
- Publication
BioMed Research International, 2014, Vol 2014, p1
- ISSN
2314-6133
- Publication type
Article
- DOI
10.1155/2014/273180