The spindle assembly checkpoint: perspectives in tumorigenesis and cancer therapy

Abstract

Loss or gain of chromosomes, a condition known as aneuploidy, is a common feature of tumor cells and has therefore been proposed as the driving force for tumorigenesis. Such chromosomal instability can arise during mitosis as a result of mis-segregation of the duplicated sister chromatids to the two daughter cells. In normal cells, missegregation is usually prevented by the spindle assembly checkpoint (SAC), a sophisticated surveillance mechanism that inhibits mitotic exit until all chromosomes have successfully achieved bipolar attachment to spindle microtubules. Complete abrogation of SAC activity is lethal to normal as well as to tumor cells, as a consequence of massive chromosome mis-segregation. Importantly, many human aneuploid tumor cells exhibit a weakened SAC activity that allows them to tolerate gains or losses of a small number of chromosomes; and interfering with this SAC residual activity may constitute a suitable strategy to kill cancer cells. This review focuses on the potential link between SAC and tumorigenesis, and the therapeutic strategy to target the SAC for cancer treatment.

Spindly and Bub3 expression in oral cancer: Prognostic and therapeutic implications

“…Bub3 overexpression has been reported in other cancers (Barbosa et al, ; Silva et al, ). High levels of Bub3 may weaken SAC signaling by altering the stoichiometric balance of SAC proteins required for MCC formation and checkpoint activity (Liu & Zhang, ).…”

“…Altered expression of many SAC components has been reported in cancer, and some of these components have been identified as suitable cancer therapeutic targets (Barbosa, Faria, Silva, & Bousbaa, ; Silva et al, ). While only scarce data have been reported concerning Bub3 expression in cancer, to the best of our knowledge, no information is available about the impact of Spindly in oral cancer pathogenesis and clinical outcome.…”

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

“…The mad2 gene is an essential component of the mitotic checkpoint, a surveillance mechanism that inhibits the metaphase-toanaphase transition whenever chromosomes are not properly attached to the mitotic spindle [8,9]. Overexpression of mad2 has been observed in several types of cancer including NSCLC, oral cancer, cervical carcinogenesis and urothelial bladder cancer [10][11][12][13].…”

Overcoming cisplatin resistance in non-small cell lung cancer with Mad2 silencing siRNA delivered systemically using EGFR-targeted chitosan nanoparticles

“…Cisplatin cytotoxicity primarily stems on its ability to interact with DNA, forming platinum-DNA adducts that inhibit DNA replication. Cell cycle checkpoints monitor the accurate order of events during cell division, including DNA damage and when an error is detected, a delay occurs to provide time for damage repair [6, 7]. Cisplatin causes arrest during cell cycle G2/M phase in cells with an intact DNA damage checkpoint [8].…”

“…Mitotic arrest deficient-2 (Mad2) is an essential component of the mitotic checkpoint that has a crucial role in the correct segregation of chromosomes during mitosis [18]. Mad2, together with other checkpoint proteins, delays anaphase until all chromosomes are attached to the mitotic spindle, assuring the fidelity of chromosome segregation in mitosis [7]. …”