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Ding Y.,Van Andel Research Institute | Huang D.,Van Andel Research Institute | Zhang Z.,Van Andel Research Institute | Smith J.,Van Andel Research Institute | And 7 more authors.
Cancer Research | Year: 2011

In recent years, several molecularly targeted therapies have been approved for clear cell renal cell carcinoma (ccRCC), a highly aggressive cancer. Although these therapies significantly extend overall survival, nearly all patients with advanced ccRCC eventually succumb to the disease. To identify other molecular targets, we profiled gene expression in 90 ccRCC patient specimens for which tumor grade information was available. Gene set enrichment analysis indicated that cell-cycle-related genes, in particular, Polo-like kinase 1 (PLK1), were associated with disease aggressiveness. We also carried out RNAi screening to identify kinases and phosphatases that when inhibited could prevent cell proliferation. As expected, RNAi-mediated knockdown of PLK1 and other cell-cycle kinases was sufficient to suppress ccRCC cell proliferation. The association of PLK1 in both disease aggression and in vitro growth prompted us to examine the effects of a small-molecule inhibitor of PLK1, BI 2536, in ccRCC cell lines. BI 2536 inhibited the proliferation of ccRCC cell lines at concentrations required to inhibit PLK1 kinase activity, and sustained inhibition of PLK1 by BI 2536 led to dramatic regression of ccRCC xenograft tumors in vivo. Taken together, these findings highlight PLK1 as a rational therapeutic target for ccRCC. ©2011 AACR. Source


Li Y.,Chinese Academy of Sciences | Zhou W.,Chinese Academy of Sciences | Wei L.,Chinese Academy of Sciences | Jin J.,Chinese Academy of Sciences | And 4 more authors.
International Journal of Oncology | Year: 2012

Aurora kinases have been shown to be involved in the regulation of the cell cycle and are related to tumor progression. This suggests the possibility that they can serve as new anticancer targets for tumor treatment. However, the important roles that Aurora kinases and their signaling pathway play in renal cell carcinoma (RCC) are not fully understood and addressed to date. In this study, we aimed to address these questions. We observed that downregulation of Aurora kinases induced by AurA miRNA, AurB miRNA or VX680 could inhibit proliferation and metastasis, induce G2/M phase arrest in clear cell renal cell carcinoma cells and exert antitumor activity in an SN12C xenograft model. We also show that either silencing of Aurora kinases or treating the cells with VX680 could downregulate the expression of cdc25c and cyclin B/cdc2, upregulate the expression of p-cdc2 (Tyr15) via blocking the activity of ERK. All these changes may contribute to inhibition of proliferation, metastasis and G2/M arrest in ccRCC. In summary, we proved that both Aurora kinases A and B are key elements of tumor growth regulation, and inhibition of Aurora kinases may contribute to blocking ccRCC progression. We conclude that Aurora kinases could be potential therapeutic targets in the management of renal cell carcinoma. Source


Nahorski M.S.,University College Birmingham | Seabra L.,University College Birmingham | Straatman-Iwanowska A.,University College London | Wingenfeld A.,Martin Luther University of Halle Wittenberg | And 7 more authors.
Human Molecular Genetics | Year: 2012

Inherited mutations in the folliculin (FLCN) gene cause the Birt-Hogg-Dubé syndrome of familial hair follicle tumours (fibrofolliculomas), lung cysts and kidney tumours. Though folliculin has features of a tumour suppressor, the precise function of the FLCN gene product is not well characterized. We identified plakophilin-4 (p0071) as a potential novel folliculin interacting protein by yeast two-hybrid analysis. We confirmed the interaction of folliculin with p0071 by co-immunoprecipitation studies and, in view of previous studies linking p0071 to the regulation of rho-signalling, cytokinesis and intercellular junction formation, we investigated the effect of cell folliculin status on p0071-related functions. Folliculin and p0071 partially co-localized at cell junctions and in mitotic cells, at the midbody during cytokinesis. Previously, p0071 has been reported to regulate RhoA signalling during cytokinesis and we found that folliculin deficiency was associated with increased expression and activity of RhoA and evidence of disordered cytokinesis. Treatment of folliculin-deficient cells with a downstream inhibitor of RhoA signalling (the ROCK inhibitor Y-27632) reversed the increased cell migration phenotype observed in folliculin-deficient cells. Deficiency of folliculin and of p0071 resulted in tight junction defects and mislocalization of E-cadherin in mouse inner medullary collecting duct-3 renal tubular cells. These findings suggest that aspects of folliculin tumour suppressor function are linked to interaction with p0071 and the regulation of RhoA signalling. © The Author 2012.Published by Oxford University Press. All rights reserved. Source


Zhou N.,Cleveland Clinic | Singh K.,Cleveland Clinic | Mir M.C.,Cleveland Clinic | Parker Y.,Cleveland Clinic | And 7 more authors.
Clinical Cancer Research | Year: 2013

Purpose: Despite more than 70,000 new cases of bladder cancer in the United States annually, patients with advanced disease have a poor prognosis due to limited treatment modalities. We evaluated Aurora kinase A, identified as an upregulated candidate molecule in bladder cancer, as a potential therapeutic target. Experimental Design: Gene expression in human bladder cancer samples was evaluated using RNA microarray and quantitative reverse transcriptase PCR. Effects of the Aurora kinase A inhibitor MLN8237 (Millennium) on cell dynamics in malignant T24 and UM-UC-3 and papilloma-derived RT4 bladder cells were evaluated in vitro and in vivo in a mouse xenograft model. Results: A set of 13 genes involved in the mitotic spindle checkpoint, including Aurora kinases A and B, were upregulated in human urothelial carcinoma compared with normal urothelium. The Aurora kinase A inhibitor MLN8237 induced cell-cycle arrest, aneuploidy, mitotic spindle failure, and apoptosis in the human bladder cancer cell lines T24 and UM-UC-3. MLN8237 also arrested tumor growth when administered orally over 4 weeks in a mouse bladder cancer xenograft model. Finally, in vitro sequential administration of MLN8237 with either paclitaxel or gemcitabine resulted in synergistic cytotoxic effects in T24 cells. Conclusions: Mitotic spindle checkpoint dysfunction is a common characteristic of human urothelial carcinoma and can be exploited with pharmacologic Aurora A inhibition. Given our demonstration of the ability of the Aurora A inhibitor MLN8237 to inhibit growth of bladder cancer in vitro and in vivo, we conclude that Aurora kinase inhibitors warrant further therapeutic investigation in bladder cancer. ©2013 AACR. Source


Zhang Z.,Van Andel Research Institute | Zhang Z.,Wistar Institute | Furge K.A.,Van Andel Research Institute | Yang X.J.,Northwestern University | And 3 more authors.
BMC Medical Genomics | Year: 2010

Background. Urothelial carcinoma (UC) can arise at any location along the urothelial tract, including the urethra, bladder, ureter, or renal pelvis. Although tumors arising in these various locations have similar morphology, it is unclear whether the gene expression profiles are similar between the upper-tract (ureter and renal pelvis) and lower-tract (bladder and urethra) carcinomas. Because differences may facilitate different screening and treatment modalities, we sought to examine the relationship between urothelial carcinoma of the renal pelvis (rUC) and urothelial carcinoma of the bladder (bUC). Methods. Fresh tumor tissue was collected from patients with bUC (n = 10) and benign mucosa from the bladder of individuals undergoing resection for non-UC conditions (n = 7). Gene expression profiles from these samples were determined using high-throughput Affymetrix gene expression microarray chips. Bioinformatic approaches were used to compare the gene expression profiles of these samples with those of rUC samples and normal kidney samples that had been described previously. Results. Using unsupervised analytic approaches, rUC and bUC were indistinguishable. Yet when a supervised analytic approach was used, a small number of differentially expressed genes were identified; these differences were most likely limited to a single pathway - the chloride ion binding activity pathway - which was more frequently activated in rUC than in bUC. Conclusions. We found that the gene expression profiles of UCs from the upper and lower tract were extremely similar, suggesting that similar pathogenic mechanisms likely function in the development of these tumors. The differential expression of genes in the identified pathway may represent a new avenue for detection of upper-tract tumors. © 2010 Zhang et al; licensee BioMed Central Ltd. Source

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