Oncotarget

Research Papers:

Investigating cytokinesis failure as a strategy in cancer therapy

Callum McKenzie _ and Pier Paolo D'Avino

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2016; 7:87323-87341. https://doi.org/10.18632/oncotarget.13556

Metrics: PDF 1729 views  |   HTML 2432 views  |   ?  


Abstract

Callum McKenzie1, Pier Paolo D’Avino1

1Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, UK

Correspondence to:

Pier Paolo D’Avino, email: [email protected]

Keywords: citron kinase, cytokinesis failure, chromosomal instability, polyploidy

Received: July 26, 2016     Accepted: November 02, 2016     Published: November 24, 2016

ABSTRACT

Effective therapeutics exploit common characteristics shared amongst cancers. As many cancers present chromosomal instability (CIN), one possible approach to treat these cancers could be to increase their CIN above a threshold that would affect their viability. Here, we investigated whether causing polyploidy by cytokinesis failure could represent a useful approach. We show that cytokinesis failure caused by depletion of Citron kinase (CIT-K) dramatically decreased cell proliferation in breast, cervical and colorectal cancer cells. CIT-K depletion activated the Hippo tumor suppressor pathway in normal, but not in cancer cells, indicating that cancer cells have evolved mechanisms to bypass this control. CIT-K depleted cancer cells died via apoptosis in a caspase 7 dependent manner and, consistent with this, p53-deficient HCT116 colon carcinoma cells failed to induce apoptosis after cytokinesis failure. However, other p53-mutated cancer cells were able to initiate apoptosis, indicating that cytokinesis failure can trigger apoptosis through a p53-independent mechanism. Finally, we found that actively dividing and, in some cases, polyploid cancer cells were more susceptible to CIT-K depletion. In sum, our findings indicate that inducing cytokinesis failure could be a promising anti-cancer therapeutic approach for a wide range of cancers, especially those characterized by fast cell proliferation and polyploidy.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 13556