Disruption of Tacc3 function leads to in vivo tumor regression

Yao, Ryoji; Natsume, Yasuko; Saiki, Yuriko; Shioya, Hisashi; Takeuchi, Kengo; Yamori, Takao; Toki, Hideaki; Aoki, Ichio; Saga, T.; Noda, Tetsuo

doi:10.1038/onc.2011.235

Cited by 36 publications

(38 citation statements)

References 44 publications

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“…Schmidt et al suggested TACC3-depleted cells arrested in G (1) through a cellular senescence program and the onset of senescence following TACC3 knockdown was remarkably accelerated in the presence of paclitaxel concentrations [13]. Moreover, Yao et al provided in vivo evidence that TACC3 loss led to tumor regression, accompanied by massive apoptosis in tumor tissue but none of overt abnormalities in normal tissues [38]. Additionally, it has been reported that high expression of TACC3 conferred cellular sensitization to radiation [39].…”

Section: Discussionmentioning

confidence: 99%

High expression of TACC3 in esophageal squamous cell carcinoma correlates with poor prognosis

et al. 2015

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To analyze the expression of the transforming acidic coiled-coil protein 3 (TACC3) in esophageal squamous cell carcinoma (ESCC) samples, and to identify whether TACC3 can serve as a biomarker for the diagnosis and prognosis of ESCC, qPCR, western blotting and immunohistochemistry staining (IHC) were utilized to detect the expression of TACC3. Furthermore, cell growth, colony formation, migration ability and the epithelial-mesenchymal transition markers of ESCC cells in which TACC3 were knocked-down were measured. The mRNA and protein levels of TACC3 were higher in ESCC specimens compared to non-tumorous esophageal epithelial tissues. IHC results revealed TACC3 expression was significantly correlated to differentiation (p = 0.017) and lymphoid nodal status (p = 0.028). The patients with high-expression of TACC3 had a significantly poor prognosis compared to those of low-expression (p = 0.017), especially in the patients at stages I–II (p = 0.028). Multivariate analysis indicated that TACC3 expression was an independent prognostic factor for ESCC patients (p = 0.025). Knockdown of TACC3 inhibited the ability of cell proliferation, colony formation and migration. This study first identifies TACC3 not only as a useful biomarker for diagnose and prognosis of ESCC, but also as a potential therapeutic target for patients with ESCC.

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Section: Discussionmentioning

confidence: 99%

High expression of TACC3 in esophageal squamous cell carcinoma correlates with poor prognosis

et al. 2015

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“…Ϫ/Ϫ sarcolymphoma model is highly effective in causing apoptotic tumor regression (76). Interestingly, besides quantitative deregulation of gene expression of TACC isoforms in several tumor types, TACC1 and TACC3 point mutants have been identified in melanoma and ovarian cancer patients (77,78).…”

Section: Discussionmentioning

confidence: 99%

The Centrosomal Adaptor TACC3 and the Microtubule Polymerase chTOG Interact via Defined C-terminal Subdomains in an Aurora-A Kinase-independent Manner

Thakur

Singh

Nagel-Steger

et al. 2014

Journal of Biological Chemistry

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Background: The TACC3-chTOG protein complex is essential for mitotic spindle assembly. Results: TACC3-chTOG binding is directed and mediated by specific intradomain and interdomain interactions that are not affected by Aurora-A kinase. Conclusion: Formation of the TACC3-chTOG complex is Aurora-A-independent, in contrast to its recruitment to the spindle apparatus. Significance: Novel insight into regulation and domain specificity of TACC3-chTOG interaction is provided.

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“…Examination of the mitotic spindle revealed numerous multipolar spindles with multiple, pericentrin-positive foci, a hallmark of TACC3 malfunction (Fig. 7C) (45). Suggesting that the combination may have efficacy in additional genetic backgrounds, cotreatment of H1299 cells with paclitaxel and KHS101 induced aberrant mitosis above levels detected for either agent alone (Fig.…”

Section: Depletion Of Testis Proteins Disrupts Bipolar Spindle Formatmentioning

confidence: 91%

Multiple Cancer Testis Antigens Function To Support Tumor Cell Mitotic Fidelity

Cappell

Sinnott

Taus

et al. 2012

Molecular and Cellular Biology

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While the expression of genes that are normally involved in spermatogenesis is frequently detected in tumors, the extent to which these gene products are required for neoplastic behaviors is unclear. To begin to address their functional relevance to tumorigenesis, we identified a cohort of proteins which display synthetic lethality with paclitaxel in non-small-cell lung cancer and whose expression is biased toward testes and tumors. Remarkably, these testis proteins, FMR1NB, NXF2, MAGEA5, FSIP1, and STARD6, are required for accurate chromosome segregation in tumor cells. Their individual depletion enhances the generation of multipolar spindles, increases mitotic transit time, and induces micronucleation in response to an otherwise innocuous dose of paclitaxel. The underlying basis for abnormal mitosis is an alteration in microtubule function, as their depletion increases microtubule cytaster formation and disrupts microtubule stability. Given these observations, we hypothesize that reactivated testis proteins may represent unique tumor cell vulnerabilities which, if targeted, could enhance responsiveness to antimitotic therapy. Indeed, we demonstrate that combining paclitaxel with a small-molecule inhibitor of the gametogenic and tumor cell mitotic protein TACC3 leads to enhanced centrosomal abnormalities, activation of death programs, and loss of anchorage-independent growth. T umor-specific epigenetic alterations allow the activation of a panoply of otherwise silenced genetic programs that can be exploited to promote neoplastic phenotypes. In particular, genes normally involved in development and gametogenesis are frequently found to be reactivated in tumors, affording an opportunity for transformed cells to co-opt primordial cell features to confer oncogenic behaviors such as self-renewal, uncontrolled proliferation, and epithelial-to-mesenchymal transition (EMT) (1, 39). Cancer testis (CT) antigens represent one group of gametogenic proteins whose expression is otherwise biased toward the testes and reactivated in tumor cells (39). Because the testes are an immune privileged site, humoral and/or cellular responses are often elicited to CT antigens in cancer patients. Thus, much focus has surrounded exploiting these antigens as anticancer vaccine targets, while functional roles, if any, for these proteins in supporting tumor cell fitness have not been extensively evaluated. There are over 200 annotated CT antigens, and most have no known role in spermatogenesis or tumorigenesis (39). However, three recent studies implicate members of the CT antigen family in tumorigenic processes, including p53 turnover, centrosome coalescence, mitotic progression, and regulation of retinoic acid signaling (10,12,43). Furthermore, high expression of specific CT antigens in tumors has been correlated with significantly poorer outcomes, suggesting that their reactivation may enhance aggressiveness or chemoresistance (8,12,43). Therefore, uncovering roles for CT antigens and other ectopically expressed gametogenic genes could si...

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Disruption of Tacc3 function leads to in vivo tumor regression

Cited by 36 publications

References 44 publications

High expression of TACC3 in esophageal squamous cell carcinoma correlates with poor prognosis

High expression of TACC3 in esophageal squamous cell carcinoma correlates with poor prognosis

The Centrosomal Adaptor TACC3 and the Microtubule Polymerase chTOG Interact via Defined C-terminal Subdomains in an Aurora-A Kinase-independent Manner

Multiple Cancer Testis Antigens Function To Support Tumor Cell Mitotic Fidelity

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