Paclitaxel-induced aberrant mitosis and mitotic slippage efficiently lead to proliferative death irrespective of canonical apoptosis and p53

Abstract

Spindle poisons elicit various cellular responses following metaphase arrest, but how they relate to longterm clonogenicity has remained unclear. We prepared several HeLa lines in which the canonical apoptosis pathway was attenuated, and compared their acute responses to paclitaxel, as well as long-term fate, with the parental line. Three-nanomolar paclitaxel induced brief metaphase arrest (<5 h) often followed by aberrant mitosis, and about 90% of the cells of each line had lost their clonogenicity after 48 h of the treatment. A combination of the same concentration of paclitaxel with the kinesin-5 inhibitor, S-trityl-L-cysteine (STLC), at 1 mM led to much longer arrest (»20 h) and predominance of subsequent linespecific responses: mitochondrial outer membrane permeabilization (MOMP) in the apoptosis-prone line, or mitotic slippage without obvious MOMP in the apoptosis-reluctant lines. In spite of this, combination with STLC did not lead to a marked difference in clonogenicity between the apoptosis-prone and -reluctant lines, and intriguingly resulted in slightly better clonogenicity than that of cells treated with 3 nM paclitaxel alone. This indicates that changes in the short-term response within 3 possible scenarios -acute MOMP, mitotic slippage or aberrant mitosis ¡ has only a weak impact on clonogenicity. Our results suggest that once cells have committed to slippage or aberrant mitosis they eventually undergo proliferative death irrespective of canonical apoptosis or p53 function. Consistent with this, cells with irregular DNA contents originating from mitotic slippage or aberrant mitosis were mostly eliminated from the population within several rounds of division after the drug treatment.

BioID-based proteomic analysis of the Bid interactome identifies novel proteins involved in cell-cycle-dependent apoptotic priming

“…However, in Taxol, MCF-7 cells predominantly underwent apoptosis, whereas MDA-MB-231 cells were prone to slippage (Supplementary Fig. S3D ), with inter- and intra-line variation consistent with previous studies 2 , 44 . We chose MCF-7 cells for generating a VDAC2 ko as these predominantly underwent death in mitosis.…”

The role of Anaphase Promoting Complex activation, inhibition and substrates in cancer development and progression

“…On the other hand, in cells harboring high loads of chromosomal instability due to excess DNA mutations, induction of mitotic slippage has been proposed as a mechanism to kill these cells. Chemicals that inhibit the SAC, such as TTKi’s [ 294 – 296 ] and M2I-1 [ 58 , 62 ], have been shown to block CDC20 sequestration by the MCC, leading to activation of the APC and effective cancer cell death. It is proposed that premature activation of the APC pushes cells with high loads of chromosome instability into mitotic division before there is time to repair the damage, causing mitotic catastrophe [ 31 ].…”

Role of Bcl‑2 on drug resistance in breast cancer polyploidy‑induced spindle poisons

“…Tumor chemotherapy is an important part of the comprehensive treatment for solid tumors (1). Paclitaxel, vincristine and other spindle poisons are widely used as first-line chemotherapy for various types of malignant tumor, such as breast cancer, cervical cancer and melanoma (2,3). One of the important methods in treating cancer is inducing tumor cell death.…”

“…The latter two phenomena are the root cause of uncontrollable tumors and recurrence. Previous studies demonstrated that spindle poisons play a role in the induction of apoptosis in some cells (2,7). However, certain cells do not undergo apoptosis when exposed to such drugs, and instead form polyploids.…”