The centrosome and mitotic spindle apparatus in cancer and senescence

Abstract

Altered cell division is associated with overproliferation and tumorigenesis, however, mitotic aberrations can also trigger antiproliferative responses leading to postmitotic cell cycle exit. Here, we focus on the role of the centrosome and in particular of centrosomal TACC (transforming acidic coiled coil) proteins in tumorigenesis and cellular senescence. We have complied recent evidence that inhibition or depletion of various mitotic proteins which take over key in centrosome and kinetochore integrity and mitotic checkpoint function in sufficient to activate a p53-p21(WAF) driven premature senescence phenotype. These findings have direct implications for proliferative tissue homeostasis as well as for cellular and organismal aging.

TACC3 promotes epithelial–mesenchymal transition (EMT) through the activation of PI3K/Akt and ERK signaling pathways

“…Similarly, overexpression of TACC3 promotes ERK signaling pathways, whereas its depletion has an opposite effect on this oncogenic signaling pathway. Since Aurora A is thought to act upstream of TACC3 [108], we speculated that the expression of TACC3 is regulated by Aurora A, thus possibly participating in Aurora A-mediated EMT process. However, we were not able to see any changes in the expression of TACC3 by modulating Aurora A (data not shown).…”

The induction of polyploidy or apoptosis by the Aurora A kinase inhibitor MK8745 is p53-dependent

“…11,16 MLN 8054 has been shown to induce cellular senescence in a p53/p21 manner. 17 However, we have shown previously that AZD 1152HQPA, a specific inhibitor of Aurora B kinase, induces polyploidy independent of p53 status of the cell line. 15,18 Even though many small-molecule inhibitors are undergoing clinical trials, it is still unclear whether polyploidy can be taken as a mechanism of cell death.…”

The involvement of MCT-1 oncoprotein in inducing mitotic catastrophe and nuclear abnormalities

“…Additionally, downregulation of mitotic spindle checkpoint kinase BubR1 by MCT-1 silencing may be also connected with p53 activation, progressive aneuploidy and post-mitotic senescence, as identified in mouse genetic study. 66 Different from p53 sufficient cells, abnormal cellular phenotypes with cytoplasmic fusion, tetraploidzation and unequal chromosome segregation revealing in MCT-1-p53 cells are potentially implicated in increase of growth rate and incidence of malignant transformation with chromosomally instability (Figs. 6C, 7D, 8B and C).…”