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Inhibition of Nek2 by small molecules affects proteasome activity
Lingyao Meng1, Kent Carpenter2, Alexis Mollard1
1Center for Investigational Therapeutics, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
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.
Insights
Novel Nek2 inhibitors overcome bortezomib resistance in multiple myeloma by targeting proteasome activity and cell cycle regulation. These findings highlight Nek2 as a promising therapeutic target for resistant cancers.
Area of Science:
- Molecular Biology
- Cancer Research
- Drug Discovery
Background:
- Nek2 kinase regulates centrosome separation and cell cycle progression (G2 to M phase).
- Elevated Nek2 expression correlates with bortezomib resistance in multiple myeloma patients.
Purpose of the Study:
- Investigate Nek2's role in bortezomib resistance.
- Identify and evaluate small-molecule Nek2 inhibitors.
Main Methods:
- Ectopic overexpression of Nek2 in cancer cell lines.
- Screening of an in-house compound library for Nek2 inhibitors.
- Assays for proteasome and cell cycle activity.
- In vitro testing of inhibitors alone and in combination with bortezomib.
Main Results:
- Nek2 overexpression increased proteasome activity.
- Nek2 inhibitors reduced proteasome activity and induced G2/M cell cycle arrest.
- Combination therapy enhanced bortezomib efficacy.
- Nek2 inhibitors mitigated bortezomib resistance in multiple myeloma models.
Conclusions:
- Nek2 is crucial for proteasome-mediated cell cycle control and bortezomib resistance.
- Nek2 represents a viable therapeutic target for bortezomib-resistant multiple myeloma.
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