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.
Highlights
Nek2 is a serine/threonine protein kinase, belonging to the NIMA-related protein kinases (Neks) family of cell cycle regulators [1]
We previously reported that bortezomib resistance is accompanied with Nek2 upregulation in MM patients [21]
The irreversible binding of HCI-2389 provides a possible explanation for this difference between compounds. These results provide evidence that proteasome activity can be inhibited to a greater extent when combining Nek2 inhibitors with bortezomib, compared to bortezomib alone, suggesting that Nek2 is a potential molecular target that might be used in combination with bortezomib to treat MM patients
Summary
Nek is a serine/threonine protein kinase, belonging to the Nek family of cell cycle regulators [1]. Nek is a serine/threonine kinase localized to the centrosome It promotes cell cycle progression from G2 to M by inducing centrosome separation. The Nek 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 Nek inhibitors with bortezomib increased the efficacy of bortezomib in decreasing proteasome activity in vitro. Nek plays a central role in proteasome-mediated cell cycle regulation and in conferring resistance to bortezomib in cancer cells. Our results introduce Nek as a therapeutic target in bortezomibresistant multiple myeloma
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
