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.
Highlights
The mitotic spindle is bipolar in nature as it is organized around two poles, each possessing a single centrosome [1, 2]
Hsp72 is required for centrosome clustering in cancer cells To examine the role of Hsp72 in centrosome clustering, we first assessed the frequency of centrosome amplification in a set of cancer and noncancer-derived cell lines using antibodies against g-tubulin to count pericentriolar material (PCM) foci and centrin-2 to score centrioles (Fig. 1A)
As VER-155008 inhibits all members of the Hsp70 family, we confirmed the specific role of the inducible Hsp72 isoform in centrosome clustering using two independent siRNA oligonucleotides to deplete the protein from MDA-MB-231 and NIE-115 cells
Summary
The mitotic spindle is bipolar in nature as it is organized around two poles, each possessing a single centrosome [1, 2]. The majority of cancer cells have extra or "amplified" centrosomes that would be expected to form multipolar spindles, leading to mitotic catastrophe and cell death [3, 4]. Cancer cells solve this problem by either inactivating the extra centrosomes or clustering them into two poles to form a pseudo-bipolar spindle [5]. Amplified centrosomes are tolerated but promote chromosome segregation errors, genome instability, and cancer progression [8,9,10].
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