Aurora B induces epithelial–mesenchymal transition by stabilizing Snail1 to promote basal-like breast cancer metastasis

Zhang, Jianchao; Lin, Xinxin; Wu, Liufeng; Huang, Jia Jia; Jiang, Wen Qi; Kipps, Thomas J.; Zhang, Suping

doi:10.1038/s41388-020-1165-z

Cited by 38 publications

(38 citation statements)

References 55 publications

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“…found that elevated Aurora B expression induces the OCT4/AKT/GSK3β/Snail1 signaling since Aurora B can activate AKT by phosphorylating of OCT4 phosphorylation site (T343), which leads to inactivation of GSK3β and Snail1 stabilization to facilitate EMT and metastasis of breast cancer. 37 Their findings also showed that targeting Aurora B with an inhibitor or by its silencing inhibits OCT4/AKT/GSK3β/Snail1 signaling and reverses EMT in TNBC cells. Other studies have reported that upregulated Aurora B induced an increase in PTK2 (FAK), AKT, PI3K, and NF-ĸB protein levels which enhanced the malignant phenotype of osteosarcoma cells via activation of the PTK2/PI3K/AKT/NF-κB pathway.…”

Section: Aurora a And Aurora Bmentioning

confidence: 95%

“…Aurora kinases A and B (here forth referred to as Aurora A or B, respectively) are a family of highly conserved serine/ threonine kinases that share a similar protein structure, a similar kinase activity, and are well known for their central role in regulating cell division. 36,37 Aurora A is essential for bipolar mitotic spindle formation, centrosome duplication and separation, chromosomal alignment, spindle assembly checkpoint, and cytokinesis, when Aurora A is inhibited cells are arrested in G2 and their mitotic entry is blocked. 36,38 Aurora B is a member of the chromosome passenger complex and regulates chromosome condensation, chromosome bi-orientation, spindle checkpoint formation, chromosome segregation, and cytokinesis.…”

Section: Aurora a And Aurora Bmentioning

confidence: 99%

“…36,38 Aurora B is a member of the chromosome passenger complex and regulates chromosome condensation, chromosome bi-orientation, spindle checkpoint formation, chromosome segregation, and cytokinesis. 37,39 Aurora B participates in several regulatory mechanisms that Col on-Marrero et al Mitotic kinases, EMT, and survival in breast cancer 1037 maintain genome stability. For example, studies have shown that Aurora B is required in the mitotic activation of the ATM kinase, an essential kinase in DNA damage response and a mitotically activated ATM phosphorylates Bub1.…”

Section: Aurora a And Aurora Bmentioning

confidence: 99%

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Mitotic kinases as drivers of the epithelial-to-mesenchymal transition and as therapeutic targets against breast cancers

Colón-Marrero

Jusino

Rivera-Rivera

et al. 2021

Exp Biol Med (Maywood)

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Biological therapies against breast cancer patients with tumors positive for the estrogen and progesterone hormone receptors and Her2 amplification have greatly improved their survival. However, to date, there are no effective biological therapies against breast cancers that lack these three receptors or triple-negative breast cancers (TNBC). TNBC correlates with poor survival, in part because they relapse following chemo- and radio-therapies. TNBC is intrinsically aggressive since they have high mitotic indexes and tend to metastasize to the central nervous system. TNBCs are more likely to display centrosome amplification, an abnormal phenotype that results in defective mitotic spindles and abnormal cytokinesis, which culminate in aneuploidy and chromosome instability (known causes of tumor initiation and chemo-resistance). Besides their known role in cell cycle control, mitotic kinases have been also studied in different types of cancer including breast, especially in the context of epithelial-to-mesenchymal transition (EMT). EMT is a cellular process characterized by the loss of cell polarity, reorganization of the cytoskeleton, and signaling reprogramming (upregulation of mesenchymal genes and downregulation of epithelial genes). Previously, we and others have shown the effects of mitotic kinases like Nek2 and Mps1 (TTK) on EMT. In this review, we focus on Aurora A, Aurora B, Bub1, and highly expressed in cancer (Hec1) as novel targets for therapeutic interventions in breast cancer and their effects on EMT. We highlight the established relationships and interactions of these and other mitotic kinases, clinical trial studies involving mitotic kinases, and the importance that represents to develop drugs against these proteins as potential targets in the primary care therapy for TNBC.

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Section: Aurora a And Aurora Bmentioning

confidence: 95%

Section: Aurora a And Aurora Bmentioning

confidence: 99%

Section: Aurora a And Aurora Bmentioning

confidence: 99%

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Mitotic kinases as drivers of the epithelial-to-mesenchymal transition and as therapeutic targets against breast cancers

Colón-Marrero

Jusino

Rivera-Rivera

et al. 2021

Exp Biol Med (Maywood)

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“…While AURKB expression was reported to be not associated with the survival of breast cancer patients [22]. Recent study demonstrated that high expression of AURKB might induce EMT in breast cancer [23]. Caspase-9 is a key caspase in intrinsic apoptosis pathway.…”

Section: Discussionmentioning

confidence: 99%

CASP9 As a Prognostic Biomarker and Promising Drug Target Plays a Pivotal Role in Inflammatory Breast Cancer

Zhang

Wang

et al. 2021

Preprint

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Background : Inflammatory breast cancer (IBC) is one of the most rare and aggressive subtype of primary breast cancer (BC). Our study aimed to explore hub genes related to the pathogenesis of IBC, which could be considered as novel molecular biomarkers for IBC diagnosis and prognosis. Material and Methods: Two datasets from gene expression omnibus database (GEO) were selected. Enrichment analysis and protein-protein interaction (PPI) network for the DEGs were performed. We analyzed the prognostic values of hub genes in the Kaplan–Meier Plotter. Connectivity Map (CMap) and Comparative Toxicogenomics Database (CTD) was used to find candidate small molecules capable to reverse the gene status of IBC. Results : 157 DEGs were selected in total. We constructed the PPI network with 154 nodes interconnected by 128 interactions. KEGG pathway analysis indicated that the DEGs were enriched in apoptosis, pathways in cancer and insulin signaling pathway. PTEN, PSMF1, PSMC6, AURKB, FZR1, CASP9, CASP6, CASP8, BAD, AKR7A2, ZNF24, SSX2IP, SIGLEC1, MS4A4A and VSIG4 were selected as hub genes based on the high degree of connectivity. Six hub genes (PSMC6, AURKB, CASP9, BAD, ZNF24 and SSX2IP) that were significantly associated with the prognosis of breast cancer. The expression of CASP9 protein was associated with prognosis and immune cells infiltration of breast cance. CASP9- naringenin (NGE) is expected to be the most promising candidate gene-compound interaction for the treatment of IBC. Conclusion : Taken together, CASP9 can be used as a prognostic biomarker and a novel therapeutic target in IBC.

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“…More recently, Gao B., et al reported that triptonide inhibits TNBC cell tumorigenesis via downregulation of several cancer stem cell-associated genes, up-regulation of Snail1 expression, and induction of a Snail1-associated feedback mechanism for triptonide resistance [37]. Of note, it is wellknown that Smail1 is aberrantly overexpressed in various types of malignant tumors including TNBC [38][39][40][41], overexpression of Snail triggers EMT [40,[42][43][44][45], carcinogenesis [46][47][48][49], and drug resistance [50,51], and is closely associated with poor prognosis in cancer patients [38,41,44,45,48,49]. Accordingly, inhibition of Snail1 in cancer has become a new strategy for developing cancer therapeutics [50][51][52].…”

Section: Introductionmentioning

confidence: 99%

Triptonide Effectively Inhibits Triple-Negative Breast Cancer Metastasis Through Concurrent Degradation Of Twist1 And Notch1 Oncoproteins

Zhang

Meng

Liu

et al. 2021

Preprint

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Background: Triple-negative breast cancer (TNBC) is highly metastatic and lethal. Due to a lack of druggable targets for this disease, there are no effective therapies in the clinic.Methods: We explored the ability of active compounds derived from natural herbs to inhibit TNBC metastasis using the methods of molecular biology, cell biology, protein chemistry, pharmacology, and xenografted mice.Results: Here, we showed that triptonide, a small molecule from the traditional Chinese medicinal herb Tripterygium wilfordii Hook F, potently inhibited TNBC cell migration, invasion, and vasculogenic mimicry, and effectively suppressed TNBC tumor growth and lung metastasis in xenografted mice with no observable toxicity. Molecular mechanistic studies revealed that triptonide strongly triggered the degradation of master epithelial-mesenchymal transition (EMT)-inducing protein Twist1 through the lysosomal system and reduced Notch1 expression and NF-κB phosphorylation, which consequently diminished the expression of pro-metastatic and angiogenic genes N-cadherin, VE-cadherin, and vascular endothelial cell growth factor receptor 2 (VEGFR2).Conclusions: Triptonide effectively suppressed TNBC cell tumorigenesis, vasculogenic mimicry, and strongly inhibited the metastasis of TNBC via degradation of Twist1 and Notch1 oncoproteins, downregulation of metastatic and angiogenic gene expression, and reduction of NF-κB signaling pathway. Our findings provide a new strategy for treating highly lethal TNBC and offer a potential new drug candidate for combatting this aggressive disease.

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Aurora B induces epithelial–mesenchymal transition by stabilizing Snail1 to promote basal-like breast cancer metastasis

Cited by 38 publications

References 55 publications

Mitotic kinases as drivers of the epithelial-to-mesenchymal transition and as therapeutic targets against breast cancers

Mitotic kinases as drivers of the epithelial-to-mesenchymal transition and as therapeutic targets against breast cancers

CASP9 As a Prognostic Biomarker and Promising Drug Target Plays a Pivotal Role in Inflammatory Breast Cancer

Triptonide Effectively Inhibits Triple-Negative Breast Cancer Metastasis Through Concurrent Degradation Of Twist1 And Notch1 Oncoproteins

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