title: Investigating cytokinesis failure as a strategy in cancer therapy.
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.
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, UK.
authors.forename: Callum
authors.initials: C
authors.lastname: McKenzie
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, CB2 1QP, UK.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: D'Avino
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D048749:Cytokinesis; D000090683:Hippo Signaling Pathway; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D016159:Tumor Suppressor Protein p53; C115635:citron-kinase; D017346:Protein Serine-Threonine Kinases
keywords: chromosomal instability; citron kinase; cytokinesis failure; polyploidy