Hsp72 and Nek6 Cooperate to Cluster Amplified Centrosomes in Cancer Cells

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Aurora Kinase A / genetics
  • Aurora Kinase A / metabolism
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Proliferation
  • Centrosome / metabolism
  • Centrosome / pathology*
  • Female
  • HSP72 Heat-Shock Proteins / genetics
  • HSP72 Heat-Shock Proteins / metabolism*
  • Humans
  • Mice
  • Mitosis / physiology
  • NIMA-Related Kinases / genetics
  • NIMA-Related Kinases / metabolism
  • Neuroblastoma / genetics
  • Neuroblastoma / metabolism
  • Neuroblastoma / pathology*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Spindle Apparatus / metabolism
  • Spindle Apparatus / pathology
  • Tumor Cells, Cultured

Substances

  • Cell Cycle Proteins
  • HSP72 Heat-Shock Proteins
  • Proto-Oncogene Proteins
  • Aurora Kinase A
  • NEK6 protein, human
  • NIMA-Related Kinases
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1