Correlation of defective mitotic checkpoint with aberrantly reduced expression of MAD2 protein in nasopharyngeal carcinoma cells

Wang, Xianghong; Jin, Dong-Yan; Wong, Yong Chuan; Cheung, Any; Chun, Abel C.S.; Lo, Angela K F; Liu, Yu; Tsao, Sai Wah

doi:10.1093/carcin/21.12.2293

Cited by 96 publications

(69 citation statements)

References 23 publications

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“…In summary, we have shown that down-regulation of MAD2, a feature common to many tumour cell lineages (Takahashi et al, 1999;Wang et al, 2000Wang et al, , 2002Fung et al, 2007) induces cellular senescence in up to a third of the cell population. Due to the fact that paclitaxel targets actively dividing cells, these cells will evade cytotoxic-induced death.…”

Section: Discussionmentioning

confidence: 53%

Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro

et al. 2009

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BACKGROUND: The mitotic arrest deficiency protein 2 (MAD2) is a key component of the mitotic spindle assembly checkpoint, monitoring accurate chromosomal alignment at the metaphase plate before mitosis. MAD2 also has a function in cellular senescence and in a cell's response to microtubule inhibitory (MI) chemotherapy exemplified by paclitaxel. METHODS: Using an siRNA approach, the impact of MAD2 down-regulation on cellular senescence and paclitaxel responsiveness was investigated. The endpoints of senescence, cell viability, migration, cytokine expression, cell cycle analysis and anaphase bridge scoring were carried out using standard approaches. RESULTS: We show that MAD2 down-regulation induces premature senescence in the MCF7 breast epithelial cancer cell line. These MAD2-depleted (MAD2k) cells are also significantly replicative incompetent but retain viability. Moreover, they show significantly higher levels of anaphase bridges and polyploidy compared to controls. In addition, these cells secrete higher levels of IL-6 and IL-8 representing key components of the senescence-associated secretory phenotype (SASP) with the ability to impact on neighbouring cells. In support of this, MAD2k cells show enhanced migratory ability. At 72 h after paclitaxel, MAD2k cells show a significant further induction of senescence compared with paclitaxel naive controls. In addition, there are significantly more viable cells in the MAD2k MCF7 cell line after paclitaxel reflecting the observed increase in senescence. CONCLUSION: Considering that paclitaxel targets actively dividing cells, these senescent cells will evade cytotoxic kill. In conclusion, compromised MAD2 levels induce a population of senescent cells resistant to paclitaxel.

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Section: Discussionmentioning

confidence: 53%

Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro

et al. 2009

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“…FAT10 has been reported to bind noncovalently to MAD2 (Liu et al, 1999), a protein necessary for maintaining spindle integrity during mitosis (Shah and Cleveland, 2000), suggesting that it may play a role in regulating genomic stability. Indeed, MAD2 dysregulation has been associated with chromosomal instability (Wang et al, 2000;Gemma et al, 2001) and has been shown to cause increased tumor incidence in mice (Michel et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…FAT10 has been shown to bind noncovalently to the human spindle assembly checkpoint protein, MAD2 (Liu et al, 1999), a protein responsible for maintaining spindle integrity during mitosis (Shah and Cleveland, 2000). The inhibition of MAD2 function has been associated with chromosomal instability, a characteristic of many cancers (Wang et al, 2000;Gemma et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Expression of the FAT10 gene is highly upregulated in hepatocellular carcinoma and other gastrointestinal and gynecological cancers

et al. 2003

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The ubiquitin-like modifier (UBL) family has recently generated much interest in the scientific community, as it is implicated to play important regulatory roles via novel protein-protein modification. FAT10 (diubiquitin) belongs to this family of proteins, comprising two ubiquitin-like moieties fused in tandem, and has been implicated to be involved in the maintenance of spindle integrity during mitosis. As FAT10 may play a role in the regulation of genomic stability, we examined if there is an association between FAT10 expression and hepatocellular carcinoma (HCC) or other cancers. Northern blot analyses revealed upregulation of FAT10 expression in the tumors of 90% of HCC patients. In situ hybridization as well as immunohistochemistry utilizing anti-FAT10 antibodies localized highest FAT10 expression in the nucleus of HCC hepatocytes rather than the surrounding immune and non-HCC cells. FAT10 expression was also found to be highly upregulated in other cancers of the gastrointestinal tract and female reproductive system. In conclusion, we demonstrated upregulation of FAT10 expression in various gastrointestinal and gynecological cancers. Its overexpression is unrelated to the general increase in protein synthesis or a general immune/ inflammatory response to cancer. Rather, FAT10 may modulate tumorigenesis through its reported interaction with the MAD2 spindle-assembly checkpoint protein.

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“…80 SAC involvement in tumorigenesis, however, is very complex and context-dependent. For instance, downregulation of SAC proteins such as Mad2 is also observed in certain liver, 81 ovarian, 82 nasopharyngeal, 83 and breast 84 cancer lines. Complete knockdown of Mad2 is embryonically lethal and results in severe aneuploidy and apoptosis in mice.…”

Section: Surviving With Surplus: Managing Supernumerary Centrosomes Bmentioning

confidence: 99%

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

2012

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Nearly a century ago, cell biologists postulated that the chromosomal aberrations blighting cancer cells might be caused by a mysterious organelle-the centrosome-that had only just been discovered. For years, however, this enigmatic structure was neglected in oncologic investigations and has only recently reemerged as a key suspect in tumorigenesis. A majority of cancer cells, unlike healthy cells, possess an amplified centrosome complement, which they manage to coalesce neatly at two spindle poles during mitosis. This clustering mechanism permits the cell to form a pseudo-bipolar mitotic spindle for segregation of sister chromatids. On rare occasions this mechanism fails, resulting in declustered centrosomes and the assembly of a multipolar spindle. Spindle multipolarity consigns the cell to an almost certain fate of mitotic arrest or death. The catastrophic nature of multipolarity has attracted efforts to develop drugs that can induce declustering in cancer cells. Such chemotherapeutics would theoretically spare healthy cells, whose normal centrosome complement should preclude multipolar spindle formation. In search of the 'Holy Grail' of nontoxic, cancer cell-selective, and superiorly efficacious chemotherapy, research is underway to elucidate the underpinnings of centrosome clustering mechanisms. Here, we detail the progress made towards that end, highlighting seminal work and suggesting directions for future research, aimed at demystifying this riddling cellular tactic and exploiting it for chemotherapeutic purposes. We also propose a model to highlight the integral role of microtubule dynamicity and the delicate balance of forces on which cancer cells rely for effective centrosome clustering. Finally, we provide insights regarding how perturbation of this balance may pave an inroad for inducing lethal centrosome dispersal and death selectively in cancer cells.

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Correlation of defective mitotic checkpoint with aberrantly reduced expression of MAD2 protein in nasopharyngeal carcinoma cells

Cited by 96 publications

References 23 publications

Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro

Cellular senescence induced by aberrant MAD2 levels impacts on paclitaxel responsiveness in vitro

Expression of the FAT10 gene is highly upregulated in hepatocellular carcinoma and other gastrointestinal and gynecological cancers

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

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