Inhibition of TACC3 by a small molecule inhibitor in breast cancer

Campo, Loredana; Breuer, Eun-Kyoung

doi:10.1016/j.bbrc.2018.03.125

Cited by 16 publications

(15 citation statements)

References 38 publications

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“…direct E-cadherin suppressors and EMT inducers (25,49,55). Pharmacological inhibition of TACC3 expression resulted in inhibition of tumor growth and invasiveness or metastasis (56)(57)(58). Chlamydia appears to induce EMT through a combination of EGFR activation and TGF-␤-mediated TACC-3 upregulation, leading to the stimulation of mesenchymal proteins and cytoskeletal reorganization.…”

Section: Discussionmentioning

confidence: 99%

Epidermal Growth Factor Receptor and Transforming Growth Factor β Signaling Pathways Cooperate To MediateChlamydiaPathogenesis

et al. 2020

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Human genital Chlamydia infection is a major public health concern due to the serious reproductive system complications. Chlamydia binds several receptor tyrosine kinases (RTKs) on host cells, including the epidermal growth factor receptor (EGFR), and activates cellular signaling cascades for host invasion, cytoskeletal remodeling, optimal inclusion development, and induction of pathogenic epithelial-mesenchyme transition (EMT). Chlamydia also upregulates transforming growth factor beta (TGF-β) expression, whose signaling pathway synergizes with the EGFR cascade, but its role in infectivity, inclusions, and EMT induction is unknown. We hypothesized that the EGFR and TGF-β signaling pathways cooperate during chlamydial infection for optimal inclusion development and stable EMT induction. The results revealed that Chlamydia upregulated TGF-β expression as early as 6 h postinfection of epithelial cells and stimulated both the EGFR and TGF-β signaling pathways. Inhibition of either the EGFR or TGF-βR1 signaling substantially reduced inclusion development; however, the combined inhibition of both EGFR and TGF-βR1 signaling reduced inclusions by over 90% and prevented EMT induction. Importantly, EGFR inhibition suppressed TGF-β expression, and an inhibitory thrombospondin-1 (Tsp1)-based peptide inhibited chlamydia-induced EMT, revealing a major source of active TGF-β during infection. Finally, TGF-βR signaling inhibition suppressed the expression of transforming acidic coiled-coil protein-3 (TACC3), which stabilizes EGFR signaling, suggesting reciprocal regulation between TGF-β and EGFR signaling during chlamydial infection. Thus, RTK-mediated host invasion by chlamydia upregulated TGF-β expression and signaling, which cooperated with other cellular signaling cascades and cytoskeletal remodeling to support optimal inclusion development and EMT induction. This finding may provide new targets for chlamydial disease biomarkers and prevention.

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Section: Discussionmentioning

confidence: 99%

Epidermal Growth Factor Receptor and Transforming Growth Factor β Signaling Pathways Cooperate To MediateChlamydiaPathogenesis

et al. 2020

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“…TACC3 overexpression is related to chemoradiotherapy resistance in patients with locally advanced rectal cancer [41]. Inhibition of TACC3 in breast cancer induced apoptotic cell death [42]. Schneider et al related TACC3 inhibition induced apoptosis to caspase-dependent cell death, in particular by activation of caspase-3 [43].…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of miR-195 and miR-497 Replacement Reveals Potential Candidates that Increase Sensitivity to Oxaliplatin in MSI/P53wt Colorectal Cancer Cells

Poel

Boyd

Beekhof

et al. 2019

Cells

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Most patients with advanced colorectal cancer (CRC) eventually develop resistance to systemic combination therapy. miR-195-5p and miR-497-5p are downregulated in CRC tissues and associated with drug resistance. Sensitization to 5-FU, oxaliplatin, and irinotecan by transfection with miR-195-5p and miR-497-5p mimics was studied using cell viability and clonogenic assays in cell lines HCT116, RKO, DLD-1, and SW480. In addition, proteomic analysis of transfected cells was implemented to identify potential targets. Significantly altered proteins were subjected to STRING (protein-protein interaction networks) database analysis to study the potential mechanisms of drug resistance. Cell viability analysis of transfected cells revealed increased sensitivity to oxaliplatin in microsatellite instable (MSI)/P53 wild-type HCT116 and RKO cells. HCT116 transfected cells formed significantly fewer colonies when treated with oxaliplatin. In sensitized cells, proteomic analysis showed 158 and 202 proteins with significantly altered expression after transfection with miR-195-5p and miR-497-5p mimics respectively, of which CHUK and LUZP1 proved to be coinciding downregulated proteins. Resistance mechanisms of these proteins may be associated with nuclear factor kappa-B signaling and G1 cell-cycle arrest. In conclusion, miR-195-5p and miR-497-5p replacement enhanced sensitivity to oxaliplatin in treatment naïve MSI/P53 wild-type CRC cells. Proteomic analysis revealed potential miRNA targets associated with the cell-cycle which possibly bare a relation with chemotherapy sensitivity.

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“…These results suggest ILK or TACC3 are good candidates for specific therapeutic targets, whilst CKAP5/ch-TOG would not be specific to cells displaying CA. Of note, recently developed TACC3 inhibitors [63,64], have not yet been tested in the context of CA.…”

Section: Proteins Required For Centrosome Clusteringmentioning

confidence: 99%

Targeting centrosome amplification, an Achilles' heel of cancer

Sabat-Pośpiech

Fabian-Kolpanowicz

Prior

et al. 2019

Biochemical Society Transactions

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Due to cell-cycle dysregulation, many cancer cells contain more than the normal compliment of centrosomes, a state referred to as centrosome amplification (CA). CA can drive oncogenic phenotypes and indeed can cause cancer in flies and mammals. However, cells have to actively manage CA, often by centrosome clustering, in order to divide. Thus, CA is also an Achilles' Heel of cancer cells. In recent years, there have been many important studies identifying proteins required for the management of CA and it has been demonstrated that disruption of some of these proteins can cause cancer-specific inhibition of cell growth. For certain targets therapeutically relevant interventions are being investigated, for example, small molecule inhibitors, although none are yet in clinical trials. As the field is now poised to move towards clinically relevant interventions, it is opportune to summarise the key work in targeting CA thus far, with particular emphasis on recent developments where small molecule or other strategies have been proposed. We also highlight the relatively unexplored paradigm of reversing CA, and thus its oncogenic effects, for therapeutic gain.

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Inhibition of TACC3 by a small molecule inhibitor in breast cancer

Cited by 16 publications

References 38 publications

Epidermal Growth Factor Receptor and Transforming Growth Factor β Signaling Pathways Cooperate To MediateChlamydiaPathogenesis

Epidermal Growth Factor Receptor and Transforming Growth Factor β Signaling Pathways Cooperate To MediateChlamydiaPathogenesis

Proteomic Analysis of miR-195 and miR-497 Replacement Reveals Potential Candidates that Increase Sensitivity to Oxaliplatin in MSI/P53wt Colorectal Cancer Cells

Targeting centrosome amplification, an Achilles' heel of cancer

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