RNAi‐mediated silencing of insulin receptor substrate‐4 enhances actinomycin D‐ and tumor necrosis factor‐α‐induced cell death in hepatocarcinoma cancer cell lines

Cuevas, Eva P.; Escribano, Óscar; Monserrat, Jorge; Martı́nez-Botas, Javier; Sánchez, María del Mar; Chiloeches, Antonio; Hernández-Breijo, Borja; Sánchez-Alonso, V.; Domingo, Alberto; Fernández‐Moreno, María Dolores; Guijarro, Luis

doi:10.1002/jcb.22359

Cited by 17 publications

(9 citation statements)

References 31 publications

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“…In contrast, we demonstrate that sorafenib is a strong inducer of CYLD expression in Huh7 and Hep3B cells (see below). Huh7 and Hep3B cells have been known to be susceptible to TNF-·-induced apoptosis in the presence of transcriptional or translational inhibitors, such as CHX, which inhibits the translation of NF-κB-dependent anti-apoptotic genes (47). In our study, we detected a reduced sensitivity of CYLD-negative HCC cells towards TNF-·-induced apoptosis.…”

Section: Discussionsupporting

confidence: 53%

Down-regulation of CYLD as a trigger for NF-κB activation and a mechanism of apoptotic resistance in hepatocellular carcinoma cells

Urbanik

Köhler²,

Boger³

et al. 2010

Int J Oncol

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Abstract. The cylindromatosis gene (CYLD) was identified as a tumor suppressor gene, which is mutated in familial cylindromatosis (Brooke-Spiegler syndrome), an autosomaldominant predisposition to multiple tumors of the skin appendages. CYLD is a deubiquitinating enzyme acting as a negative regulator of the nuclear factor κB (NF-κB) signaling pathway by removing lysine-63-linked polyubiquitin chains from NF-κB activating proteins. In order to investigate the role of CYLD in apoptotic signaling in human hepatocellular carcinoma (HCC) cells, we first studied the expression levels of CYLD in HCC tissues. CYLD expression was lower in HCC both at protein and mRNA levels compared to the surrounding non-malignant tissue. In order to further study the role of CYLD in the apoptotic sensitivity of HCC cells, CYLD was specifically down-regulated in HCC cell lines via RNA interference. The specific down-regulation of CYLD resulted in increased resistance towards treatment with doxorubicin, 5-fluorouracil and cisplatin. In addition, the downregulation of CYLD in HCC cells decreased the sensitivity towards tumor necrosis factor-·-induced apoptosis. The CYLD knockdown also led to the degradation of the NF-κB inhibitor, IκB-·, resulting in enhanced NF-κB activity in HCC cells. Finally, we found that CYLD expression was triggered by the multikinase inhibitor, sorafenib, by the inhibition of Raf-1, as well as by the blockage of the prosurvival kinases, MEK (U0126) and the epidermal growth factor receptor (AG1478). In summary, we show that CYLD is down-regulated in human HCC and is involved in the apoptotic resistance of HCC cells. Our data indentify the reconstitution of CYLD expression as an attractive approach for overcoming resistance to treatment in HCC.

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Section: Discussionsupporting

confidence: 53%

Down-regulation of CYLD as a trigger for NF-κB activation and a mechanism of apoptotic resistance in hepatocellular carcinoma cells

Urbanik

Köhler²,

Boger³

et al. 2010

Int J Oncol

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“…16,17 In addition, challenge to the practical application of RNA interference therapy in human tumors is to define a targeted method of siRNA delivery specifically to reach the cytoplasm of cancer cells. 8,18 Systemic delivery systems such as retrovirus or adenovirus can target tumor cells well, but are limited to research use in animal models due to human safety issues.…”

Section: Discussionmentioning

confidence: 99%

Targeted therapy via oral administration of attenuated Salmonella expression plasmid-vectored Stat3-shRNA cures orthotopically transplanted mouse HCC

et al. 2012

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The development of RNA interference-based cancer gene therapies has been delayed due to the lack of effective tumor-targeting delivery systems. Attenuated Salmonella enterica serovar Typhimurium (S. Typhimurium) has a natural tropism for solid tumors. We report here the use of attenuated S. Typhimurium as a vector to deliver shRNA directly into tumor cells. Constitutively activated signal transducer and activator of transcription 3 (Stat3) is a key transcription factor involved in both hepatocellular carcinoma (HCC) growth and metastasis. In this study, attenuated S. Typhimurium was capable of delivering shRNA-expressing vectors to the targeted cancer cells and inducing RNA interference in vivo. More importantly, a single oral dose of attenuated S. Typhimurium carrying shRNA-expressing vectors targeting Stat3 induced remarkably delayed and reduced HCC (in 70% of mice). Cancer in these cured mice did not recur over 2 years following treatment. These data demonstrated that RNA interference combined with Salmonella as a delivery system may offer a novel clinical approach for cancer gene therapy.

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“…It is a gene whose expression has not been detectable in mice (Qu et al 1999) and is also linked with tumor growth and proliferation (Cuevas et al 2009; Mardilovich et al 2009). However, little is known about the function of this gene, with previous attempts failing to identify a tissue type containing detectable levels of expression (Schreyer 2003).…”

Section: Resultsmentioning

confidence: 99%

The Evolution of Human Cells in Terms of Protein Innovation

Sardar

Oates

Fang

et al. 2014

Molecular Biology and Evolution

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Humans are composed of hundreds of cell types. As the genomic DNA of each somatic cell is identical, cell type is determined by what is expressed and when. Until recently, little has been reported about the determinants of human cell identity, particularly from the joint perspective of gene evolution and expression. Here, we chart the evolutionary past of all documented human cell types via the collective histories of proteins, the principal product of gene expression. FANTOM5 data provide cell-type–specific digital expression of human protein-coding genes and the SUPERFAMILY resource is used to provide protein domain annotation. The evolutionary epoch in which each protein was created is inferred by comparison with domain annotation of all other completely sequenced genomes. Studying the distribution across epochs of genes expressed in each cell type reveals insights into human cellular evolution in terms of protein innovation. For each cell type, its history of protein innovation is charted based on the genes it expresses. Combining the histories of all cell types enables us to create a timeline of cell evolution. This timeline identifies the possibility that our common ancestor Coelomata (cavity-forming animals) provided the innovation required for the innate immune system, whereas cells which now form the brain of human have followed a trajectory of continually accumulating novel proteins since Opisthokonta (boundary of animals and fungi). We conclude that exaptation of existing domain architectures into new contexts is the dominant source of cell-type–specific domain architectures.

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RNAi‐mediated silencing of insulin receptor substrate‐4 enhances actinomycin D‐ and tumor necrosis factor‐α‐induced cell death in hepatocarcinoma cancer cell lines

Cited by 17 publications

References 31 publications

Down-regulation of CYLD as a trigger for NF-κB activation and a mechanism of apoptotic resistance in hepatocellular carcinoma cells

Down-regulation of CYLD as a trigger for NF-κB activation and a mechanism of apoptotic resistance in hepatocellular carcinoma cells

Targeted therapy via oral administration of attenuated Salmonella expression plasmid-vectored Stat3-shRNA cures orthotopically transplanted mouse HCC

The Evolution of Human Cells in Terms of Protein Innovation

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