Format

Send to

Choose Destination
Cancer Res. 2017 Sep 15;77(18):4785-4796. doi: 10.1158/0008-5472.CAN-16-3233. Epub 2017 Jul 18.

Hsp72 and Nek6 Cooperate to Cluster Amplified Centrosomes in Cancer Cells.

Author information

1
Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom.
2
Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom.
3
Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
4
Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom. amf5@le.ac.uk.

Abstract

Cancer cells frequently possess extra amplified centrosomes clustered into two poles whose pseudo-bipolar spindles exhibit reduced fidelity of chromosome segregation and promote genetic instability. Inhibition of centrosome clustering triggers multipolar spindle formation and mitotic catastrophe, offering an attractive therapeutic approach to selectively kill cells with amplified centrosomes. However, mechanisms of centrosome clustering remain poorly understood. Here, we identify a new pathway that acts through NIMA-related kinase 6 (Nek6) and Hsp72 to promote centrosome clustering. Nek6, as well as its upstream activators polo-like kinase 1 and Aurora-A, targeted Hsp72 to the poles of cells with amplified centrosomes. Unlike some centrosome declustering agents, blocking Hsp72 or Nek6 function did not induce formation of acentrosomal poles, meaning that multipolar spindles were observable only in cells with amplified centrosomes. Inhibition of Hsp72 in acute lymphoblastic leukemia cells resulted in increased multipolar spindle frequency that correlated with centrosome amplification, while loss of Hsp72 or Nek6 function in noncancer-derived cells disturbs neither spindle formation nor mitotic progression. Hence, the Nek6-Hsp72 module represents a novel actionable pathway for selective targeting of cancer cells with amplified centrosomes. Cancer Res; 77(18); 4785-96. ©2017 AACR.

PMID:
28720575
DOI:
10.1158/0008-5472.CAN-16-3233
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center