Mitotic catastrophe and endomitosis in tumour cells: An evolutionary key to a molecular solution

Abstract

Following genotoxic insult, p53 mutated tumour cells undergo mitotic catastrophe. This is characterised by a switch from mitosis to the endocycle. The essential difference between mitosis and the endocycle is that in the latter, DNA synthesis is uncoupled from cell division, which leads to the formation of endopolyploid cells. Recent data suggests that a return from the endocycle into mitosis is also possible. Furthermore, our observations indicate that a particular type of endocycle known as endomitosis may be involved in this return. Here we review the role of endomitosis in the somatic reduction of polyploidy during development and its postulated role in the evolution of meiosis. Finally, we incorporate these evolutionary data to help interpret our most recent observations in the tumour cell system, which indicate a role for endomitosis and meiotic regulators, in particular p39mos in the segregation of genomes (somatic reduction) of these endopolyploid cells.

Chromosomal breaks during mitotic catastrophe trigger γH2AX–ATM–p53-mediated apoptosis

“…In this scenario, cells display a multinucleated and/or micronucleated morphology (Erenpreisa et al, 2005). A detailed microscopic investigation of nuclear morphology revealed that doxorubicin-induced MC in 14-3-3s-knockout HCT116 cells led to an accumulation of cells containing either nuclei united around a single microtubuleorganising centre with extensive protrusions or blebs, or several micronuclei, which lacked this connection (Fig.…”

“…The latter is a process occurring either during or shortly after a dysregulated or failed mitosis, and can be accompanied by morphological alterations, including micronucleation (which often results from chromosomes and/or chromosome fragments that have not been distributed evenly between daughter nuclei) and multinucleation (the presence of two or more nuclei with similar or heterogeneous sizes, deriving from a deficient separation during cytokinesis). Tumour cells forced to undergo MC have also been shown to enter an endocyclic process, in which they uncouple DNA replication from the S-phase of the cell cycle and form endopolyploid mononucleated giant cells (Erenpreisa et al, 2005;Waldman et al, 1996;Yu, 1964). The stage of mitosis during which cells start to undergo MC seems to be important for the decision to form various morphological abnormalities specific to MC.…”

AMPK: Evidence for an energy-sensing cytokinetic tumor suppressor

“…We are currently evaluating if parasexual somatic reduction (i.e., nuclear budding or "neosis") [23][24][25] and/or sexual reduction (i.e., meiosis) 26,27 could explain how metformin-induced giant polyploid cells efficiently evade death via mitotic catastrophe. 28,29 Because polyploidization by endocycles of DNA synthesis in the absence of cytokinesis may increase the cell mass and metabolic output and might confer survival value on the cell, these on-going experimental models may reveal how molecular co-evolution of the energy-sensing cytokinetic tumor suppressor AMPK within the AMPK activating biophysical constraints of the tumor microenvironment may provide a "metabolic mode" to generate new progenies of tumor-initiating cells with stem cell-like properties.…”

Mitotic catastrophe induced by overexpression of budding yeast Rad2p

“…However, the endonuclease activity of Rad2p was dispensable for cell growth arrest by Rad2p. Furthermore, Rad2p-induced cells displayed a characteristic morphology of mitotic catastrophe and endomitosis, which is defined as DNA synthesis without coordinated cell division (Erenpreisa et al, 2005). DNA content and DAPI analysis verified that a significant portion of the cell population contained more than double the normal DNA content.…”