The Mitotic Kinase Aurora-A Induces Mammary Cell Migration and Breast Cancer Metastasis by Activating the Cofilin-F-actin Pathway

Wang, Lihui; Xiang, Jin; Yan, Min; Zhang, Yan; Zhao, Yan; Yue, Cai Feng; Xu, Jie; Zheng, Fei-Meng; Chen, Jin Na; Kang, Zhuang; Chen, Tong Sheng; Xing, Da; Liu, Quentin

doi:10.1158/0008-5472.can-10-1246

Cited by 111 publications

(109 citation statements)

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“…34 In addition, we have recently found that AURKA induced cell survival and migration. 7,8,12 In this study, we demonstrated that AURKA inhibited autophagy in breast cancer cells. Autophagy inhibition promoted tumorigenesis that has been reported in ovarian, breast and prostate cancers.…”

Section: Vx-680 (mentioning

confidence: 53%

“…7 To assess whether AURKA increased MTOR activity dependent on the PtdIns3K-AKT1 pathway, the SK-BR-3 cells stably overexpressing AURKA and control cells were treated with the irreversible PtdIns3K inhibitor wortmanin (10 μM) and AKT1 signaling inhibitor-2 (API-2, 15 μM) for 24 h respectively. Both wortmannin and API-2 failed to prevent the increase in phosphorylated MTOR expression caused by AURKA overexpression (Fig.…”

Section: Vx-680 (mentioning

confidence: 99%

“…5 Our recent studies indicated that overexpression of AURKA is involved in laryngeal, nasopharyngeal and breast cancer cell metastasis. [6][7][8] Moreover, high AURKA expression induces chemoresistance in breast cancer cells and ovarian cancer cells. 9,10 Our previous studies suggest that targeting AURKA may be of therapeutic use, leading to apoptosis in acute myeloid leukemia and tongue squamous cell carcinoma.…”

Section: Introductionmentioning

confidence: 99%

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Aurora kinase A inhibition-induced autophagy triggers drug resistance in breast cancer cells

et al. 2012

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Section: Vx-680 (mentioning

confidence: 53%

Section: Vx-680 (mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Aurora kinase A inhibition-induced autophagy triggers drug resistance in breast cancer cells

et al. 2012

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“…The Aurora family kinases, especially aurora-A, play a particularly important role in the cell cycle and their deregulated expression is involved in many types of human malignancies [47,48]. Several studies showed that aurora-A overexpression correlates with tumorigenesis, metastasis, and chemoresistance, confirming its pro-survival function in cancer cells [49][50][51]. Although in the literature there is evidence describing the activation of AURKA in different tumors, the mechanism of transcriptional upregulation of AURKA in human BC is not yet elucidated [15].…”

Section: Discussionmentioning

confidence: 99%

HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions

Fanale

Bazan

Corsini

et al. 2013

Breast Cancer Res Treat

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Numerous microarray-based gene expression studies performed on several types of solid tumors revealed significant changes in key genes involved in progression and regulation of the cell cycle, including AURKA that is known to be overexpressed in many types of human malignancies. Tumor hypoxia is associated with poor prognosis in several cancer types, including breast cancer (BC). Since hypoxia is a condition that influences the expression of many genes involved in tumorigenesis, proliferation, and cell cycle regulation, we performed a microarray-based gene expression analysis in order to identify differentially expressed genes in BC cell lines exposed to hypoxia. This analysis showed that hypoxia induces a down-regulation of AURKA expression. Although hypoxia is a tumor feature, the molecular mechanisms that regulate AURKA expression in response to hypoxia in BC are still unknown. For the first time, we demonstrated that HIF-1 activation downstream of hypoxia could drive AURKA down-regulation in BC cells. In fact, we found that siRNA-mediated knockdown of HIF-1a significantly reduces the AURKA down-regulation in BC cells under hypoxia. The aim of our study was to obtain new insights into AURKA transcriptional regulation in hypoxic conditions. Luciferase reporter assays showed a reduction of AURKA promoter activity in hypoxia. Unlike the previous findings, we hypothesize a new possible mechanism where HIF-1, rather than inducing transcriptional activation, could promote the AURKA down-regulation via its binding to hypoxia-responsive elements into the proximal region of the AURKA promoter. The present study shows that hypoxia directly links HIF-1 with AURKA expression, suggesting a possible pathophysiological role of this new pathway in BC and confirming HIF-1 as an important player linking an environmental signal to the AURKA promoter. Since AURKA down-regulation overrides the estrogen-mediated growth and chemoresistance in BC cells, these findings could be important for the development of new possible therapies against BC.

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“…(32) We previously reported that Aurora-A induced epithelial-mesenchymal transition and invasion was mediated by activating cofilin and MAPK signaling. (33,44) Moreover, high Aurora-A mRNA levels were inversely associated with tumor stage and distant metastasis (P < 0.001) in oral, pharyngeal, and laryngeal squamous cell carcinomas. (30) Here, we proved that overexpression of Aurora-A predicted an inferior OS and DMFS, indicating that Aurora-A-induced survival disadvantage might be attributed to its distinctive capacity in enhancing cancer cell migration to distant areas for NPC and other types of HNSCC.…”

Section: P-valuementioning

confidence: 99%

Aurora‐A activation, correlated with hypoxia‐inducible factor‐1α, promotes radiochemoresistance and predicts poor outcome for nasopharyngeal carcinoma

et al. 2012

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Previously, we and others showed that hypoxia-inducible factor-1a (HIF-1a) and transcriptionally upregulated Aurora-A were required for disease progression in several tumors. Here, we address the clinicopathologic value of Aurora-A and HIF-1a in locally advanced nasopharyngeal carcinoma (NPC). Aurora-A and HIF-1a expression was semiquantitatively evaluated by immunohistochemistry staining in 144 cases from a randomized controlled trial. Of these patients, 69 received neoadjuvant chemotherapy plus concurrent chemoradiotherapy, and acted as the training set, and 75 cases treated with neoadjuvant chemotherapy plus radiotherapy were used as the testing set to validate the prognostic effect of Aurora-A and HIF-1a. We found that Aurora-A and HIF-1a were highly expressed in NPC, but were deficient in normal adjacent epithelia. In the testing set, Aurora-A overexpression predicted a shortened 5-year overall survival (59.1% vs 82.5%, P = 0.024), progressionfree survival (44.8% vs 79.8%, P = 0.004), and distant metastasisfree survival (43.0% vs 17.3%, P = 0.016). Multivariate regression analysis confirmed that Aurora-A was indeed an independent prognostic factor for death, recurrence, and distant metastasis both in the testing set and overall patients. Moreover, a positive correlation between Aurora-A and HIF-1a was detected (P = 0.037). Importantly, although HIF-1a did not show any prognostic effect for patient outcome, the subset with Aurora-A and HIF-1a co-overexpression had the poorest overall, progression-free, and distant metastasis-free survival (all P < 0.05). Our results confirmed that Aurora-A was an independent prognostic factor for NPC. Aurora-A combined with HIF-1a refined the risk definition of the patient subset, thus potentially directing locally advanced NPC patients for more selective therapy. (Cancer Sci 2012; 103: 1586-1594

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The Mitotic Kinase Aurora-A Induces Mammary Cell Migration and Breast Cancer Metastasis by Activating the Cofilin-F-actin Pathway

Cited by 111 publications

References 45 publications

Aurora kinase A inhibition-induced autophagy triggers drug resistance in breast cancer cells

Aurora kinase A inhibition-induced autophagy triggers drug resistance in breast cancer cells

HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions

Aurora‐A activation, correlated with hypoxia‐inducible factor‐1α, promotes radiochemoresistance and predicts poor outcome for nasopharyngeal carcinoma

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