Depression of MAD2 inhibits apoptosis and increases proliferation and multidrug resistance in gastric cancer cells by regulating the activation of phosphorylated survivin

Wang, Li; Yin, Fei; Du, Yulei; Chen, Bei; Liang, Shuhui; Zhang, Yongguo; Du, Wei; Wu, Kaichun; Ding, Jie; Fan, Daiming

doi:10.1007/s13277-010-0036-6

Cited by 19 publications

(15 citation statements)

References 33 publications

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“…13). Notably, we found that other FAT10-induced malignant characteristics such as enhanced proliferation, migration, and invasion and resistance to apoptosis also were dependent on its interaction with MAD2, consistent with the reported promalignant phenotype of MAD2-deficient cells (34)(35)(36). These findings suggest that MAD2 may have other roles that are independent of its role in mitosis, although the underlying mechanisms at present remain unclear.…”

Section: Discussionsupporting

confidence: 87%

Disruption of FAT10–MAD2 binding inhibits tumor progression

Theng

Wang

Mah

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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FAT10 (HLA-F-adjacent transcript 10) is a ubiquitin-like modifier that is commonly overexpressed in various tumors. It was found to play a role in mitotic regulation through its interaction with mitotic arrestdeficient 2 (MAD2). Overexpression of FAT10 promotes tumor growth and malignancy. Here, we identified the MAD2-binding interface of FAT10 to be located on its first ubiquitin-like domain whose NMR structure thus was determined. We further proceeded to demonstrate that disruption of the FAT10-MAD2 interaction through mutation of specific MAD2-binding residues did not interfere with the interaction of FAT10 with its other known interacting partners. Significantly, ablation of the FAT10-MAD2 interaction dramatically limited the promalignant capacity of FAT10, including promoting tumor growth in vivo and inducing aneuploidy, proliferation, migration, invasion, and resistance to apoptosis in vitro. Our results strongly suggest that the interaction of FAT10 with MAD2 is a key mechanism underlying the promalignant property of FAT10 and offer prospects for the development of anticancer strategies.chromosomal instability | ubiquitin | aneuploidy | cancer progression | FAT10 F AT10 (HLA-F-adjacent transcript 10) is a ubiquitin-like modifier protein that functions as a proteasomal degradation signal (1-3). Recent studies, however, have suggested that FAT10's functions extend beyond protein degradation. FAT10 is expressed mainly in tissues of the immune system, including the spleen and thymus (4, 5). In immune cells, FAT10 is strongly induced by proinflammatory stimuli and facilitates T-cell activation by enhancing antigen presentation of mature dendritic cells (6). FAT10 also is induced by proinflammatory cytokines in various tissues outside the immune system including the liver and colon (7,8), although the physiological functions of this response remain unknown. What is clear, however, is that constitutive induction of FAT10 has deleterious consequences in promoting cellular malignancy. Our group recently has reported that ectopic expression of FAT10 induced malignant transformation in nontumorigenic cells and tumor promotion in tumorigenic cells (9), implicating FAT10 in facilitating tumor growth and progression. This finding is consistent with multiple reports that found FAT10 to be up-regulated in several tumor types including tumors of the liver and colon (5,8,10,11).To date, the mechanism underlying FAT10's promalignant characteristic remains unclear. One compelling albeit indirect piece of evidence stems from the finding that FAT10 interacts with the spindle checkpoint protein mitotic arrest-deficient 2 (MAD2) during mitosis and reduces MAD2 localization to the kinetochores, resulting in aneuploidy (7, 12), a phenomenon closely associated with tumorigenesis and a hallmark of many solid tumors (13). Given the strong association between aneuploidy, chromosomal instability, and cancer development (reviewed in ref. 14), we hypothesized that FAT10 induces malignant progression through its interaction with MAD2. The...

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Section: Discussionsupporting

confidence: 87%

Disruption of FAT10–MAD2 binding inhibits tumor progression

Theng

Wang

Mah

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Many researchers have suggested that frequent inactivation of the mitotic spindle checkpoint in cancer might contribute to the resistance of tumor cells to chemotherapeutics [23] . Because elevated Hec1 expression was observed in various cancers, multiple studies have endeavored to identify the effects on tumor therapy and chemoresistance.…”

Section: Wwwchinapharcom Mo Qq Et Almentioning

confidence: 99%

Inhibition of Hec1 expression enhances the sensitivity of human ovarian cancer cells to paclitaxel

Chen

Jin

et al. 2013

Acta Pharmacol Sin

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Aim: Hec1, a member of the Ndc80 kinetochore complex, is highly expressed in cancers. The aim of this study was to explore the role and mechanism of action of Hec1 with respect to the cytotoxicity of paclitaxel in ovarian cancer. Methods: Thirty ovarian cancer samples and 6 normal ovarian samples were collected. Hec1 expression in these samples was determined with immunohistochemistry. Ovarian cancer cell lines A2780, OV2008, C13K, SKOV3, and CAOV3 and A2780/Taxol were examined. Cell apoptosis and cell cycle analysis were detected with flow cytometric technique. siRNA was used to delete Hec1 in the cells. The expression of related mRNAs and proteins was measured using RT-PCR and Western blot analysis, respectively. Results: Hec1 expression was significantly higher in ovarian cancer samples than in normal ovarian samples, and was associated with paclitaxel-resistance and poor prognosis. Among the 6 ovarian cancer cell lines examined, Hec1 expression was highest in paclitaxelresistant A2780/Taxol cells, and lowest in A2780 cells. Depleting Hec1 in A2780/Taxol cells with siRNA decreased the IC 50 value of paclitaxel by more than 10-fold (from 590±26.7 to 45.6±19.4 nmol/L). Depleting Hec1 in A2780 cells had no significant effect on the paclitaxel sensitivity. In paclitaxel-treated A2780/Taxol cells, depleting Hec1 significantly increased the cleaved PARP and Bax protein levels, and decreased the Bcl-xL protein level. Conclusion: Hec1 overexpression is associated with the progression and poor prognosis of ovarian cancer. Inhibition of Hec1 expression can sensitize ovarian cancer cells to paclitaxel.

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“…however, chemotherapeutic drugs resistance is still a problem. Overexpression of survivin has been shown to contribute to drug-resistance [30][31][32]. Chemotherapeutic drugs inducing g2-M arrest with elevated or residual p34 cdc2 kinase activity caused Thr 34 phosphoralation and increased survivin levels [33].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Survivin mutant Thr34Ala induces apoptosis and inhibits gastric cancer growth

Dang¹,

Feng²,

Wang³

et al. 2015

neo

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Survivin is highly expressed in human gastric cancer cells and correlated with chemoresistance and poor prognosis. in this study, we explored the effect of adeno-associated virus (aaV)-mediated survivin dominant mutant Thr34ala (raaV-SurMut(T34a)) on gastric cancer growth. aaV-Sur-Mut (T34a) virus was generated and purified using the aaV vector paM/ Cag-WPRe.poly(a) vector. Cell proliferation was determined by the 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay. apoptosis was determined by Flow cytometry and Terminal deoxynucleotidyl transferase duTP nick end labeling. gene expression was determined by Western blot and immunohistochemistry. Tumor growth was evaluated using a xenograft mouse model. Overexpression of survivin promoted cell growth of gastric cancer cells. infection of raaVSur-Mut(T34a) virus inhibited cell proliferation, induced apoptosis and sensitized gastric cancer cells to 5-Fluorouracil in vitro. Treatment of raaV-Sur-Mut(T34a) significantly inhibited cell proliferation, induced apoptosis and inhibited gastric cancer growth in vivo. Our results suggest that the combination of raaV-Sur-Mut(T34a) and chemotherapy may be a new approach for gastric cancer therapy.

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Depression of MAD2 inhibits apoptosis and increases proliferation and multidrug resistance in gastric cancer cells by regulating the activation of phosphorylated survivin

Cited by 19 publications

References 33 publications

Disruption of FAT10–MAD2 binding inhibits tumor progression

Disruption of FAT10–MAD2 binding inhibits tumor progression

Inhibition of Hec1 expression enhances the sensitivity of human ovarian cancer cells to paclitaxel

Overexpression of Survivin mutant Thr34Ala induces apoptosis and inhibits gastric cancer growth

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