Targeting Integrin-Linked Kinase Suppresses Invasion and Metastasis through Downregulation of Epithelial-to-Mesenchymal Transition in Renal Cell Carcinoma

Han, Kyung Seok; Li, Na; Raven, Peter A.; Fazli, Ladan; Ettinger, Susan; Hong, Sung Joon; Gleave, Martin; So, Alan

doi:10.1158/1535-7163.mct-14-0771

Cited by 23 publications

(20 citation statements)

References 39 publications

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“…MCF-7 and MDA-MB-231 breast cancer cells treated with a combination of suberoylbis-hydroxamic acid (SBHA) and a proteasome inhibitor had significantly higher p53 , Bax, Bcl-xS and Bak protein levels and decreased the Bcl-2 level [91]. A combination of TSA and TRAIL effectively increased caspase-3, -8, and -9 activation and degradation, in human RCC Caki cells [92]. Our results clearly suggested that TSA, PdNPs or the combination of TSA and PdNPs increased the expression of caspase-3 and -9.…”

Section: Resultsmentioning

confidence: 99%

Trichostatin A Enhances the Apoptotic Potential of Palladium Nanoparticles in Human Cervical Cancer Cells

Zhang

Shen

et al. 2016

IJMS

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Cervical cancer ranks seventh overall among all types of cancer in women. Although several treatments, including radiation, surgery and chemotherapy, are available to eradicate or reduce the size of cancer, many cancers eventually relapse. Thus, it is essential to identify possible alternative therapeutic approaches for cancer. We sought to identify alternative and effective therapeutic approaches, by first synthesizing palladium nanoparticles (PdNPs), using a novel biomolecule called saponin. The synthesized PdNPs were characterized by several analytical techniques. They were significantly spherical in shape, with an average size of 5 nm. Recently, PdNPs gained much interest in various therapies of cancer cells. Similarly, histone deacetylase inhibitors are known to play a vital role in anti-proliferative activity, gene expression, cell cycle arrest, differentiation and apoptosis in various cancer cells. Therefore, we selected trichostatin A (TSA) and PdNPs and studied their combined effect on apoptosis in cervical cancer cells. Cells treated with either TSA or PdNPs showed a dose-dependent effect on cell viability. The combinatorial effect, tested with 50 nM TSA and 50 nMPdNPs, had a more dramatic inhibitory effect on cell viability, than either TSA or PdNPs alone. The combination of TSA and PdNPs had a more pronounced effect on cytotoxicity, oxidative stress, mitochondrial membrane potential (MMP), caspase-3/9 activity and expression of pro- and anti-apoptotic genes. Our data show a strong synergistic interaction between TSA and PdNPs in cervical cancer cells. The combinatorial treatment increased the therapeutic potential and demonstrated relevant targeted therapy for cervical cancer. Furthermore, we provide the first evidence for the combinatory effect and cytotoxicity mechanism of TSA and PdNPs in cervical cancer cells.

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Section: Resultsmentioning

confidence: 99%

Trichostatin A Enhances the Apoptotic Potential of Palladium Nanoparticles in Human Cervical Cancer Cells

Zhang

Shen

et al. 2016

IJMS

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“…19–21 Additionally, ILK has been shown previously to activate MLC through phosphorylation, 13,14 thereby affecting cell adhesion and migration. Studies have demonstrated previously that ROCK kinase also regulates MLC phosphorylation; thus, MLC may serve as an important signaling node in regulating cancer cell motility, potentially being targeted by T315.…”

Section: Discussionmentioning

confidence: 99%

Integrin-linked kinase affects signaling pathways and migration in thyroid cancer cells and is a potential therapeutic target

Shirley

McCarty

Yang

et al. 2016

Surgery

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Background Integrin-linked kinase (ILK) is a serine-threonine kinase that regulates interactions between the cell and the extracellular matrix. In many cancers, overexpression of ILK leads to increased cell proliferation, motility, and invasion. We hypothesized that ILK functions as a regulator of viability and migration in thyroid cancer cells. Methods Eleven human thyroid cancer cell lines were screened for ILK protein expression. The cell lines with the greatest expression were treated with either ILK small interfering RNA (siRNA) or a novel ILK inhibitor, T315, and the effects were evaluated via Western blot and migration assay. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assays were performed to assess cell viability. Results siRNA against ILK decreased phosphorylation of downstream effectors Akt and MLC, as well as decreased migration. Treatment with T315 showed a dose-related decrease in both Akt and MLC phosphorylation, as well as decreased migration. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assays showed T315 to have an half maximal inhibitory concentration of less than 1 µM in cell lines with high ILK expression. Conclusion ILK is expressed differentially in thyroid cancer cell lines. Both ILK siRNA and T315 inhibit motility of thyroid cancer cell lines, and T315 is shown to be cytotoxic at low concentrations. Altogether, our study suggests that ILK may represent an important kinase in aggressive thyroid cancers.

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“…EMT-TF such as snail, slug and ZEB1 are the spotlight of EMT investigation [13]. Upregulation of ZEB1 has been observed in various cancers and the expression of ZEB1 is significantly correlated to tumor grade and lymphatic or distant metastasis [22][23][24]. Previous studies showed that ZEB1 induces EMT by binding to the promoter of E-cadherin and depressing the expression level of E-cadherin.…”

Section: Discussionmentioning

confidence: 99%

CEP55 promotes epithelial–mesenchymal transition in renal cell carcinoma through PI3K/AKT/mTOR pathway

et al. 2019

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Purpose To study the detailed mechanisms of tumorigenesis and clinical outcomes of centrosomal protein 55 (CEP55) overexpression in renal cell carcinoma. Materials and methods Microarray analysis was performed to explore differentially expressed genes in five pairs of RCC tissues. Data of CEP55 expression and corresponding clinical information for 532 RCC patients of TCGA database were downloaded from cBioPortal. The expression of CEP55 in RCC tissues and cells was determined by real-time quantitative reverse transcription PCR (qRT-PCR), Western blot analysis and immunohistochemistry (IHC). Cells were transfected with siRNAs or lentivirus to regulate the expression of CEP55. The effects of CEP55 on proliferation, migration, invasion and epithelial-to-mesenchymal transition (EMT) of RCC cells were determined by MTS, migration and invasion assay and Western blot analysis. Results CEP55, one of the most upregulated genes in microarray analysis, was overexpressed in RCC tissues and cells. CEP55 expression was significantly correlated with poor outcome including neoplasm disease stage, histologic grade and TNM status, as well as survival status of patients. In vitro experiments showed that downregulation of CEP55 could dramatically inhibit RCC cell proliferation, migration and invasion, while overexpression of CEP55 could promote these biological behaviors. We further demonstrated that CEP55 knockdown suppressed epithelial-mesenchymal transition (EMT), which was mediated via upregulation of E-cadherin and downregulation of N-cadherin and ZEB1, through PI3K/AKT/mTOR pathway. In contrast, overexpression of CEP55 could promote EMT in RCC cells via the activation of PI3K/AKT/mTOR pathway. Importantly, inhibition of PI3K/AKT/mTOR pathway reduced the effects of CEP55 on the migration, invasion and EMT of RCC cells. Conclusion Our study showed that CEP55 could promote EMT through PI3K/AKT/mTOR pathway and might be an effective prognostic marker in RCC.

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Targeting Integrin-Linked Kinase Suppresses Invasion and Metastasis through Downregulation of Epithelial-to-Mesenchymal Transition in Renal Cell Carcinoma

Cited by 23 publications

References 39 publications

Trichostatin A Enhances the Apoptotic Potential of Palladium Nanoparticles in Human Cervical Cancer Cells

Trichostatin A Enhances the Apoptotic Potential of Palladium Nanoparticles in Human Cervical Cancer Cells

Integrin-linked kinase affects signaling pathways and migration in thyroid cancer cells and is a potential therapeutic target

CEP55 promotes epithelial–mesenchymal transition in renal cell carcinoma through PI3K/AKT/mTOR pathway

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