Failed cytokinesis leads to tetraploidy, which is an important intermediate preceding aneuploidy and the onset of tumorigenesis. The centrosome is required for the completion of cytokinesis through the transport of important components to the midbody; however, the identity of molecular components and the mechanism involved remains poorly understood. In this study, we report that the peptidyl prolyl isomerase cyclophilin A (cypA) is a centrosome protein that undergoes cell cycle-dependent relocation to the midzone and midbody during cytokinesis in Jurkat cells implicating a role during division. Depletion of cypA does not disrupt mitotic spindle formation or progression through anaphase; however, it leads to cytokinesis defects through an inability to resolve intercellular bridges, culminating in delayed or failed cytokinesis. Defective cytokinesis is also evident by an increased prevalence of midbody-arrested cells. Expression of wild-type cypA reverses the cytokinesis defect in knockout cells, whereas an isomerase mutant does not, indicating that the isomerisation activity of cypA is required for cytokinesis. In contrast, wild-type cypA and the isomerase mutant localize to the centrosome and midbody, suggesting that localization to these structures is independent of isomerase activity. Depletion of cypA also generates tetraploid cells and supernumerary centrosomes. Finally, colony formation in soft agar is impaired in cypA-knockout cells, suggesting that cypA confers clonogenic advantage on tumor cells. Collectively, this data reveals a novel role for cypA isomerase activity in the completion of cytokinesis and the maintenance of genome stability.

Titanocene compounds are a novel series of agents that exhibit cytotoxic effects in a variety of human cancer cells in vitro and in vivo. In this study, the antiproliferative activity of two titanocenes (Titanocenes X and Y) was evaluated in human epidermoid cancer cells in vitro. Titanocenes X and Y induce apoptotic cell death in epidermoid cancer cells, with IC50 values that are comparable to cisplatin. Characterisation of the cell death pathway induced by titanocene compounds in A431 cells revealed that apoptosis is preceded by cell cycle arrest and the inhibition of cell proliferation. The induction of apoptosis is dependent on the activation of caspase-3 and -7 but not caspase-8. Furthermore, the antitumour activity of Titanocene Y was tested in an A431 xenograft model of epidermoid cancer. Results indicate that Titanocene Y significantly reduced the growth of A431 xenografts with an antitumour effect similar to cisplatin. These results suggest that titanocenes represent a novel series of promising antitumour agents.

The role of aneuploidy in tumorigenesis remains poorly understood, although the two have been known to be linked for more than 100 years. Recent studies indicate that aneuploidy can promote tumour cell growth and cell death and that the cellular outcome is dependent on the extent of aneuploidy induced. The mitotic checkpoint plays a pivotal role in the maintenance of genome stability and has been the focus of work investigating the distinct outcomes of aneuploidy. In the present article, we review the molecular mechanisms involved and discuss the potential of the mitotic checkpoint as a therapeutic target in cancer therapy.

Microtubule assembly and disassembly is required for the maintenance of cell structure, mobility, and division. However, the cellular and biochemical implications of microtubule disruption are not fully understood. Using a proteomic approach, we found that the peptidyl-prolyl isomerase, cyclophilin A, was increased in plasma membrane extracts from chronic myeloid leukemia cells after microtubule disruption. In addition, we found that two peptidyl-prolyl isomerases, cyclophilin A and pin1, are overexpressed up to 10-fold in hematological malignancies compared with normal peripheral blood mononuclear cells. Although previous reports suggest that cyclophilin A is localized to the cytosol of mammalian cells, we found that cyclophilin A and pin1 are both localized to the nucleus and nuclear domains in hematopoietic cells. Microtubule disruption of hematopoietic cells caused a dramatic subcellular redistribution of cyclophilin A and pin1 from the nucleus to the cytosol and plasma membrane. We suggest that this accounts for the increased cyclophilin A at the plasma membrane of chronic myeloid leukemia cells after microtubule disruption. The subcellular redistribution of cyclophilin A and pin1 occurred in a c-Jun NH 2 -terminal kinase-and serine protease-dependent manner. Moreover, the altered subcellular localization of the peptidyl-prolyl isomerases occurred in a dose-and time-dependent manner after microtubule disruption and was found to correlate with G 2 /M arrest and precede induced cell death. These results suggest that the function of peptidyl-prolyl isomerases may be influenced by microtubule dynamics throughout the cell cycle, and their altered localization may be an important part of the mechanism by which microtubuledisrupting agents exert their cytostatic effects.