Stress Proteins and Pancreatic Cancer Metastasis

Cano, Carla E.; Iovanna, Juan

doi:10.1100/tsw.2010.186

Cited by 15 publications

(14 citation statements)

References 45 publications

(47 reference statements)

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“…15 In this case, the nanoparticles could be acting on the Nupri1 gene, which encodes p8 protein in order to prevent cell death. 16 Therefore, the presented results demonstrate that Ce NP pretreatment prevented cell death and increased cell viability upon starvation stress. This indicates that nano-CeO 2 might stimulate cell survivor mechanisms, such as higher expression of p8 and Bcl-2 proteins.…”

Section: Discussionmentioning

confidence: 54%

Increased viability of fibroblasts when pretreated with ceria nanoparticles during serum deprivation

Genier

Bizanek

Webster

et al. 2018

IJN

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Conditions of cellular stress are often the cause of cell death or dysfunction. Sustained cell stress can lead to several health complications, such as extensive inflammatory responses, tumor growth, and necrosis. To prevent disease and protect human tissue during these conditions and to avoid medication side effects, nanomaterials with unique characteristics have been applied to biological systems. This paper introduces the pretreatment in human dermal fibroblasts with cerium oxide nanoparticles during nutritional stress. For this purpose, human dermal fibroblast cells received cell culture media with concentrations of 250 µg/mL and 500 µg/mL of nano-cerium oxide before being exposed to 24, 48, and 72 hours of serum starvation. Contrast images demonstrated higher cell confluence and cell integrity in cells pretreated with ceria nanoparticles compared to untreated cells. It was confirmed by MTS assay after 72 hours of serum starvation that higher cell viability was achieved with ceria nanoparticles. The results demonstrate the potential of cerium oxide nanoparticles as protective agents during cellular starvation.

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Section: Discussionmentioning

confidence: 54%

Increased viability of fibroblasts when pretreated with ceria nanoparticles during serum deprivation

Genier

Bizanek

Webster

et al. 2018

IJN

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“…It has been reported that NUPR1 is involved in chemoresistance in breast and pancreatic cancers. 38, 39 Here we demonstrated that NUPR1 depletion led to a significant increase in HCC cell sensitivity to sorafenib treatment, suggesting that it may also have a pivotal role in HCC chemoresistance.…”

Section: Discussionmentioning

confidence: 66%

NUPR1, a new target in liver cancer: implication in controlling cell growth, migration, invasion and sorafenib resistance

et al. 2016

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Sorafenib, an oral multikinase inhibitor, is the only approved agent for the treatment of advanced hepatocellular carcinoma (HCC). However, its benefits are modest, and as its mechanisms of action remain elusive, a better understanding of its anticancer effects is needed. Based on our previous study results, we investigated here the implication of the nuclear protein 1 (NUPR1) in HCC and its role in sorafenib treatment. NUPR1 is a stress-inducible protein that is overexpressed in various malignancies, but its role in HCC is not yet fully understood. We found that NUPR1 expression was significantly higher in primary human HCC samples than in the normal liver. Knockdown of NUPR1 significantly increased cell sensitivity to sorafenib and inhibited the cell growth, migration and invasion of HCC cells, both in vitro and in vivo. Moreover, NUPR1 silencing influenced the expression of RELB and IER3 genes. Unsurprisingly, RELB and IER3 knockdown also inhibited HCC cell viability, growth and migration. Using gene expression profiling of HCC cells following stable NUPR1 knockdown, we found that genes functionally involved in cell death and survival, cellular response to therapies, lipid metabolism, cell growth and proliferation, molecular transport and cellular movement were mostly suppressed. Network analysis of dynamic gene expression identified NF-κB and ERK as downregulated gene nodes, and several HCC-related oncogenes were also suppressed. We identified Runt-related transcription factor 2 (RUNX2) gene as a NUPR1-regulated gene and demonstrated that RUNX2 gene silencing inhibits HCC cell viability, growth, migration and increased cell sensitivity to sorafenib. We propose that the NUPR1/RELB/IER3/RUNX2 pathway has a pivotal role in hepatocarcinogenesis. The identification of the NUPR1/RELB/IER3/RUNX2 pathway as a potential therapeutic target may contribute to the development of new treatment strategies for HCC management.

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“…For instance, we reported Nupr1 antiapoptotic function against the anticancer drug gemcitabine (23), which is at present the first choice for PDAC treatment. Nupr1 regulates in part the cell response to stress through the modulation of target gene expression (24). In addition, Nupr1 regulates chromatin accessibility through its interaction with proteins implicated in histone acetylation/deacetylation and may thereby modulate the genetic response to stress (25).…”

Section: Introductionmentioning

confidence: 99%

Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis

et al. 2012

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Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all cancers and shows remarkable resistance to cell stress. Nuclear protein 1 (Nupr1), which mediates stress response in the pancreas, is frequently upregulated in pancreatic cancer. Here, we report that Nupr1 plays an essential role in pancreatic tumorigenesis. In a mouse model of pancreatic cancer with constitutively expressed oncogenic Kras G12D , we found that loss of Nupr1 protected from the development of pancreatic intraepithelial neoplasias (PanINs). Further, in cultured pancreatic cells, nutrient deprivation activated Nupr1 expression, which we found to be required for cell survival. We found that Nupr1 protected cells from stress-induced death by inhibiting apoptosis through a pathway dependent on transcription factor RelB and immediate early response 3 (IER3). NUPR1, RELB, and IER3 proteins were coexpressed in mouse PanINs from Kras G12D -expressing pancreas. Moreover, pancreasspecific deletion of Relb in a Kras G12D background resulted in delayed in PanIN development associated with a lack of IER3 expression. Thus, efficient PanIN formation was dependent on the expression of Nupr1 and Relb, with likely involvement of IER3. Finally, in patients with PDAC, expression of NUPR1, RELB, and IER3 was significantly correlated with a poor prognosis. Cumulatively, these results reveal a NUPR1/RELB/IER3 stressrelated pathway that is required for oncogenic Kras G12D -dependent transformation of the pancreas. IntroductionPancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate and the lowest overall survival of all cancers (less than 3%-4% at 5 years). The incidence of PDAC almost equals its mortality rate and is increasing every year, with more than 38,000 predicted new cases in the United States and 65,000 in Europe. Surgery is the most effective treatment, but the mean life expectancy of the 15%-20% of patients who present with a resectable tumor is only 15-18 months (1). Even for patients eligible for surgery, aggressive metastasis often appears after operation, and survival of patients with metastatic disease is only 3-6 months (2). Chemotherapy and radiotherapy offer limited benefit for patients undergoing surgery in metastatic disease (3). Most strategies tested so far for the treatment of PDAC have consisted of using therapies that show some efficacy in other carcinomas, but none of them improved significantly the overall survival of PDAC patients. Hence, in order to develop new, efficient therapies against PDAC, future research must take into account PDAC specificities such as its remarkable resistance to cell stress, notably to the stress induced by chemotherapy and radiotherapy (4), and the preponderant presence of a fibrotic stroma, which favors tumor progression by creating a barrier against drug delivery and

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Stress Proteins and Pancreatic Cancer Metastasis

Cited by 15 publications

References 45 publications

Increased viability of fibroblasts when pretreated with ceria nanoparticles during serum deprivation

Increased viability of fibroblasts when pretreated with ceria nanoparticles during serum deprivation

NUPR1, a new target in liver cancer: implication in controlling cell growth, migration, invasion and sorafenib resistance

Nuclear protein 1 promotes pancreatic cancer development and protects cells from stress by inhibiting apoptosis

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