Stressing Mitosis to Death

Abstract

The final stage of cell division (mitosis), involves the compaction of the duplicated genome into chromatid pairs. Each pair is captured by microtubules emanating from opposite spindle poles, aligned at the metaphase plate, and then faithfully segregated to form two identical daughter cells. Chromatids that are not correctly attached to the spindle are detected by the constitutively active spindle assembly checkpoint (SAC). Any stress that prevents correct bipolar spindle attachment, blocks the satisfaction of the SAC, and induces a prolonged mitotic arrest, providing the cell time to obtain attachment and complete segregation correctly. Unfortunately, during mitosis repairing damage is not generally possible due to the compaction of DNA into chromosomes, and subsequent suppression of gene transcription and translation. Therefore, in the presence of significant damage cell death is instigated to ensure that genomic stability is maintained. While most stresses lead to an arrest in mitosis, some promote premature mitotic exit, allowing cells to bypass mitotic cell death. This mini-review will focus on the effects and outcomes that common stresses have on mitosis, and how this impacts on the efficacy of mitotic chemotherapies.

c‐Rel is a cell cycle modulator in human melanoma cells

“…SAC assures correct chromosome distribution to two developing daughter cells by controlling microtubule attachment of the mitotic spindle to the chromosomes prior to mitotic anaphase . After prolonged SAC activation and concomitant arrest in early mitotic stages, the cell can trigger “mitotic slippage” resulting in a tetraploid (polyploid) cell status . Thus, the increase in polyploid c‐Rel‐suppressed melanoma cells in our studies may be the result of unresolved problems during mitotic progression.…”

“…[47] After prolonged SAC activation and concomitant arrest in early mitotic stages, the cell can trigger "mitotic slippage" resulting in a tetraploid (polyploid) cell status. [48] Thus, the increase in and chromosome alignment defects, [49] overexpression of mutant BRAF (BRAF V600E ) induced multipolar mitotic spindle formation and supernumerary centrosomes and therefore has been associated with aneuploidy and chromosomal instability. [50] In general, cells with aberrant mitotic spindles may undergo three possible fates: either mitotic cell death, mitotic slippage or even continuation of mitosis after error correction.…”

Biodistribution and Pharmacokinetics of Mad2 siRNA-loaded EGFR-Targeted Chitosan Nanoparticles in Cisplatin Sensitive and Resistant Lung Cancer Models

“…Mad2 depletion disrupts mitotic checkpoint function leading to premature mitotic exit, increased chromosome fragmentation and Biodistribution and pharmacokinetics of Mad2 siRNA-loaded EGFR-targeted chitosan nanoparticles in cisplatin sensitive and resistant lung cancer models extensive cell death, and also sensitizes cancer cells to anticancer drugs. [14][15][16]. We recently used RNA interference (RNAi) approach to highlight the potential of mad2 gene knockdown as antitumor therapeutic strategy [14].…”

Health effects of desalinated water: Role of electrolyte disturbance in cancer development

“…The swelling of mitotic cells by exposure to hypotonic conditions has been shown to arrest the mitotic process (Huges, 1952;Burgess et al, 2014). Under hypotonic stress, the arrest is far less stable (than under hypertonic stress) and enables cells to rapidly undergo mitotic slippage, characterized by chromosome decondensation, disrupted kinetochore and spindle structure, and reformation of the nuclear envelope around un-segregated chromosomes (Brinkley et al, 1980;Ford and Congedi, 1987), all of which promote genomic instability through chromosome aberrations and polyploidy (Nowak, 1987;Burgess et al, 2014). Via this pathway, exposure to hypotonic stress can increase the susceptibility of cells to carcinogenesis and this mitotic feature has led to efforts to use hypotonic solutions to increase the uptake of chemotherapies (platinumbased treatments such as Taxol) by cancer cells (Stephen et al, 1990;Katano et al, 1997).…”

“…Osmotic stress can have a strong influence on the final stage of cell division (mitosis) when the duplicated genome is compacted into chromatid pairs (Burgess et al, 2014). The swelling of mitotic cells by exposure to hypotonic conditions has been shown to arrest the mitotic process (Huges, 1952;Burgess et al, 2014).…”