Activation of Meiosis-Specific Genes Is Associated with Depolyploidization of Human Tumor Cells following Radiation-Induced Mitotic Catastrophe

Abstract

Cancer is frequently characterized histologically by the appearance of large cells that are either aneuploid or polyploid. Aneuploidy and polyploidy are hallmarks of radiation-induced mitotic catastrophe (MC), a common phenomenon occurring in tumor cells with impaired p53 function following exposure to various cytotoxic and genotoxic agents. MC is characterized by altered expression of mitotic regulators, untimely and abnormal cell division, delayed DNA damage, and changes in morphology. We report here that cells undergoing radiation-induced MC are more plastic with regards to ploidy and that this plasticity allows them to reorganize their genetic material through reduction division to produce smaller cells which are morphologically indistinguishable from control cells. Experiments conducted with the large-scale digital cell analysis system are discussed and show that a small fraction of polyploid cancer cells formed via radiation-induced MC can survive and start a process of depolyploidization that yields various outcomes. Although most multipolar divisions failed and cell fusion occurred, some of these divisions were successful and originated a variety of cell progeny characterized by different ploidy. Among these ploidy phenotypes, a progeny of small mononucleated cells, indistinguishable from the untreated control cells, is often seen. We report here evidence that meiosis-specific genes are expressed in the polyploid cells during depolyploidization. Tumor cells might take advantage of the temporary change from a promitotic to a promeiotic division regimen to facilitate depolyploidization and restore the proliferative state of the tumor cell population. These events might be mechanisms by which tumor progression and resistance to treatment occur in vivo.

MOS, aneuploidy and the ploidy cycle of cancer cells

“…Cohesion of sister centromeres by the meiotic cohesin Rec8 was found in ETC of a human lymphoma cell line undergoing reduction divisions after a period of intensive homologous DNA repair involving the mitotic/meiotic recombinases Rad51 and DMC1 (Ivanov et al, 2003;Erenpreisa et al, 2009;Ianzini et al, 2009).…”

“…Many meiotic genes have now been observed to be upregulated in genotoxically stressed lymphoma, HeLa and breast cancer human cell lines including MOS, REC8, SGO1 and SPO11 Kalejs et al, 2006;Ianzini et al, 2009;Erenpreisa et al, 2009). It is interesting to note then, that mutations in genes involved in homologous recombination, sister chromatid cohesion and spindle formation were amongst the few revealed as polyploidy-specific lethal in a large-scale genetic screen in yeast (Storchovaé t al., 2006).…”

AMPK: Evidence for an energy-sensing cytokinetic tumor suppressor

“…Intriguingly, a preliminary assessment of p53-null A431 (polyploid) pools with acquired auto-resistance to the CRM metformin has revealed an unexpected phenotype: the generation of haploid cells. 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.…”

Cell Cycle Modification in Trophoblast Cell Populations in the Course of Placenta Formation

“…Therefore, restitutive divisions of large (endopolyploid) cells represent a possibility that the tumor can recover post-treatment and start up again (Whetley, 2006). Upregulation of meiosis-specific genes, such as REC8, MOS, and SPO11, was demonstrated in these cells (Kalejs et al, 2006;Ianzini et al, 2009). Besides, signs of pluripotency and selfrenewal stem cell genes NANOG, OCT4, and SOX2 in this polyploidy-dependent survival mechanism were found (Erenpreisa, Cragg, 2010).…”