scholarly journals Anti-Allergic Drug Suppressed Pancreatic Carcinogenesis via Down-Regulation of Cellular Proliferation

2021 ◽  
Vol 22 (14) ◽  
pp. 7444
Author(s):  
Kenta Kachi ◽  
Hiroyuki Kato ◽  
Aya Naiki-Ito ◽  
Masayuki Komura ◽  
Aya Nagano-Matsuo ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cellular Proliferation ◽  
Ductal Adenocarcinoma ◽  
High Dose ◽  
Dependent Manner ◽  
Leukotriene D4 ◽  
Pancreatic Carcinogenesis ◽  
Pancreatic Cancer Cells ◽  
Chemopreventive Effect

Pancreatic cancer is a fatal disease, and thus its chemoprevention is an important issue. Based on the recent report that patients with allergic diseases have a low risk for pancreatic cancer, we examined the potential chemopreventive effect of anti-allergic agents using a hamster pancreatic carcinogenesis model. Among the three anti-allergic drugs administered, montelukast showed a tendency to suppress the incidence of pancreatic cancer. Further animal study revealed a significantly decreased incidence of pancreatic cancer in the high-dose montelukast group compared with controls. The development of the pancreatic intraepithelial neoplasia lesions was also significantly suppressed. The Ki-67 labeling index was significantly lower in pancreatic carcinomas in the high-dose montelukast group than in controls. In vitro experiments revealed that montelukast suppressed proliferation of pancreatic cancer cells in a dose-dependent manner with decreased expression of phospho-ERK1/2. Montelukast induced G1 phase arrest. Conversely, leukotriene D4 (LTD4), an agonist of CYSLTR1, increased cellular proliferation of pancreatic cancer cells with an accumulation of phospho-ERK1/2. In our cohort, pancreatic ductal adenocarcinoma patients with high CYSLTR1 expression showed a significantly unfavorable clinical outcome compared with those with low expression. Our results indicate that montelukast exerts a chemopreventive effect on pancreatic cancer via the LTD4–CYSLTR1 axis and has potential for treatment of pancreatic carcinogenesis.

scholarly journals ROCK2 Confers Acquired Gemcitabine Resistance in Pancreatic Cancer Cells by Upregulating Transcription Factor ZEB1

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1881 ◽  
Author(s):  
Yang Zhou ◽  
Yunjiang Zhou ◽  
Keke Wang ◽  
Tao Li ◽  
Minda Zhang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Transcriptional Activation ◽  
Coiled Coil ◽  
Ductal Adenocarcinoma ◽  
Dependent Manner ◽  
Promoter Regions ◽  
Gemcitabine Resistance ◽  
Pancreatic Cancer Cells ◽  
Or Gene

Resistance to chemotherapy is a major clinical challenge in the treatment of pancreatic ductal adenocarcinoma (PDAC). Here, we provide evidence that Rho associated coiled-coil containing protein kinase 2 (ROCK2) maintains gemcitabine resistance in gemcitabine resistant pancreatic cancer cells (GR cells). Pharmacological inhibition or gene silencing of ROCK2 markedly sensitized GR cells to gemcitabine by suppressing the expression of zinc-finger-enhancer binding protein 1 (ZEB1). Mechanically, ROCK2-induced sp1 phosphorylation at Thr-453 enhanced the ability of sp1 binding to ZEB1 promoter regions in a p38-dependent manner. Moreover, transcriptional activation of ZEB1 facilitated GR cells to repair gemcitabine-mediated DNA damage via ATM/p-CHK1 signaling pathway. Our findings demonstrate the essential role of ROCK2 in EMT-induced gemcitabine resistance in pancreatic cancer cells and provide strong evidence for the clinical application of fasudil, a ROCK2 inhibitor, in gemcitabine-refractory PDAC.

Galectin-3 is modulated in pancreatic cancer cells under hypoxia and nutrient deprivation

2020 ◽  
Vol 401 (10) ◽  
pp. 1153-1165 ◽  
Author(s):  
Antônio F. da Silva Filho ◽  
Lucas B. Tavares ◽  
Maira G. R. Pitta ◽  
Eduardo I. C. Beltrão ◽  
Moacyr J. B. M. Rêgo
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
Mrna Expression ◽  
Cancer Cells ◽  
Ductal Adenocarcinoma ◽  
Reverse Transcription Pcr ◽  
Pancreatic Cancer Cells ◽  
Through Flow ◽  
Galectin 3

AbstractPancreatic ductal adenocarcinoma is one of the most aggressive tumors with a microenvironment marked by hypoxia and starvation. Galectin-3 has been evaluated in solid tumors and seems to present both pro/anti-tumor effects. So, this study aims to characterize the expression of Galectin-3 from pancreatic tumor cells and analyze its influence for cell survive and motility in mimetic microenvironment. For this, cell cycle and cell death were accessed through flow cytometry. Characterization of inside and outside Galectin-3 was performed through Real-Time Quantitative Reverse Transcription PCR (qRT-PCR), immunofluorescence, Western blot, and ELISA. Consequences of Galectin-3 extracellular inhibition were investigated using cell death and scratch assays. PANC-1 showed increased Galectin-3 mRNA expression when cultivated in hypoxia for 24 and 48 h. After 24 h in simultaneously hypoxic/deprived incubation, PANC-1 shows increased Galectin-3 protein and secreted levels. For Mia PaCa-2, cultivation in deprivation was determinant for the increasing in Galectin-3 mRNA expression. When cultivated in simultaneously hypoxic/deprived condition, Mia PaCa-2 also presented increasing for the Galectin-3 secreted levels. Treatment of PANC-1 cells with lactose increased the death rate when cells were incubated simultaneously hypoxic/deprived condition. Therefore, it is possible to conclude that the microenvironmental conditions modulate the Galectin-3 expression on the transcriptional and translational levels for pancreatic cancer cells.

scholarly journals NR5A2 transcriptional activation by BRD4 promotes pancreatic cancer progression by upregulating GDF15

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Feng Guo ◽  
Yingke Zhou ◽  
Hui Guo ◽  
Dianyun Ren ◽  
Xin Jin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Transcriptional Activation ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
Gene Sets ◽  
And Migration

AbstractNR5A2 is a transcription factor regulating the expression of various oncogenes. However, the role of NR5A2 and the specific regulatory mechanism of NR5A2 in pancreatic ductal adenocarcinoma (PDAC) are not thoroughly studied. In our study, Western blotting, real-time PCR, and immunohistochemistry were conducted to assess the expression levels of different molecules. Wound-healing, MTS, colony formation, and transwell assays were employed to evaluate the malignant potential of pancreatic cancer cells. We demonstrated that NR5A2 acted as a negative prognostic biomarker in PDAC. NR5A2 silencing inhibited the proliferation and migration abilities of pancreatic cancer cells in vitro and in vivo. While NR5A2 overexpression markedly promoted both events in vitro. We further identified that NR5A2 was transcriptionally upregulated by BRD4 in pancreatic cancer cells and this was confirmed by Chromatin immunoprecipitation (ChIP) and ChIP-qPCR. Besides, transcriptome RNA sequencing (RNA-Seq) was performed to explore the cancer-promoting effects of NR5A2, we found that GDF15 is a component of multiple down-regulated tumor-promoting gene sets after NR5A2 was silenced. Next, we showed that NR5A2 enhanced the malignancy of pancreatic cancer cells by inducing the transcription of GDF15. Collectively, our findings suggest that NR5A2 expression is induced by BRD4. In turn, NR5A2 activates the transcription of GDF15, promoting pancreatic cancer progression. Therefore, NR5A2 and GDF15 could be promising therapeutic targets in pancreatic cancer.

Hyperglycemia Promotes Pancreatic Cancer Initiation and Progression by Activating the Wnt/β-Catenin Signaling Pathway

2021 ◽  
Vol 21 ◽  
Author(s):  
Huiming Chen ◽  
Junfeng Zhao ◽  
Ningning Jiang ◽  
Zheng Wang ◽  
Chang Liu
Keyword(s):  
Pancreatic Cancer ◽  
Signaling Pathway ◽  
Precancerous Lesions ◽  
Clinical Specimen ◽  
Ductal Adenocarcinoma ◽  
Dependent Manner ◽  
Pancreatic Cancer Cells ◽  
Cancer Initiation

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases, with a 5-year survival rate of less than 10% because of the limited knowledge of tumor-promoting factors and their underlying mechanism. Diabetes mellitus (DM) and hyperglycemia are risk factors for many cancers, including PDAC, that modulate multiple downstream signaling pathways, such as the wingless/integrated (Wnt)/β-catenin signaling pathway. However, whether hyperglycemia promotes PDAC initiation and progression by activating the Wnt/β-catenin signaling pathway remains unclear. Methods: In this study, we used bioinformatics analysis and clinical specimen analysis to evaluate the activation states of the Wnt/βcatenin signaling pathway. In addition, colony formation assays, Transwell assays and wound-healing assays were used to evaluate the malignant biological behaviors of pancreatic cancer cells (PCs) under hyperglycemic conditions. To describe the effects of hyperglycemia and the Wnt/β-catenin signaling pathway on the initiation of PDAC, we used pancreatitis-driven pancreatic cancer initiation models in vivo and pancreatic acinar cell 3-dimensional culture in vitro. Results: Wnt/β-catenin signaling pathway-related molecules were overexpressed in PDAC tissues/cells and correlated with poor prognosis in PDAC patients. In addition, hyperglycemia exacerbated the abnormal activation of β-catenin in PDAC and enhanced the malignant biological behaviors of PCs in a Wnt/β-catenin signaling pathway-dependent manner. Indeed, hyperglycemia accelerated the formation of pancreatic precancerous lesions by activating the Wnt/β-catenin signaling pathway in vivo and in vitro. Conclusion: Hyperglycemia promotes pancreatic cancer initiation and progression by activating the Wnt/β-catenin signaling pathway.

scholarly journals Metabolic plasticity imparts erlotinib-resistance in pancreatic cancer by upregulating glucose-6-phosphate dehydrogenase

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Neha Sharma ◽  
Alok Bhushan ◽  
Jun He ◽  
Gagan Kaushal ◽  
Vikas Bhardwaj
Keyword(s):  
Pancreatic Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Treatment Options ◽  
Pentose Phosphate ◽  
Metabolic Phenotype ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Resistant Cells

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant forms of cancer. Lack of effective treatment options and drug resistance contributes to the low survival among PDAC patients. In this study, we investigated the metabolic alterations in pancreatic cancer cells that do not respond to the EGFR inhibitor erlotinib. We selected erlotinib-resistant pancreatic cancer cells from MiaPaCa2 and AsPC1 cell lines. Metabolic profiling of erlotinib-resistant cells revealed a significant downregulation of glycolytic activity and reduced level of glycolytic metabolites compared to the sensitive cells. The resistant cells displayed elevated expression of the pentose phosphate pathway (PPP) enzymes involved in ROS regulation and nucleotide biosynthesis. The enhanced PPP elevated cellular NADPH/NADP+ ratio and protected the cells from reactive oxygen species (ROS)-induced damage. Inhibition of PPP using 6-aminonicotinamide (6AN) elevated ROS levels, induced G1 cell cycle arrest, and sensitized resistant cells to erlotinib. Genetic studies identified elevated PPP enzyme glucose-6-phosphate dehydrogenase (G6PD) as an important contributor to erlotinib resistance. Mechanistically, our data showed that upregulation of inhibitor of differentiation (ID1) regulates G6PD expression in resistant cells thus contributing to altered metabolic phenotype and reduced response to erlotinib. Together, our results highlight an underlying role of tumor metabolism in PDAC drug response and identify G6PD as a target to overcome drug resistance.

scholarly journals Glucose Metabolism in Pancreatic Cancer

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1460 ◽  
Author(s):  
Liang Yan ◽  
Priyank Raj ◽  
Wantong Yao ◽  
Haoqiang Ying
Keyword(s):  
Pancreatic Cancer ◽  
Glucose Metabolism ◽  
Cancer Cells ◽  
Redox Homeostasis ◽  
Central Carbon Metabolism ◽  
Ductal Adenocarcinoma ◽  
Glycolytic Flux ◽  
Pancreatic Cancer Cells ◽  
Cellular Energetics ◽  
Salvage Pathways

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers, with a five-year survival rate of around 5% to 8%. To date, very few available drugs have been successfully used to treat PDAC due to the poor understanding of the tumor-specific features. One of the hallmarks of pancreatic cancer cells is the deregulated cellular energetics characterized by the “Warburg effect”. It has been known for decades that cancer cells have a dramatically increased glycolytic flux even in the presence of oxygen and normal mitochondrial function. Glycolytic flux is the central carbon metabolism process in all cells, which not only produces adenosine triphosphate (ATP) but also provides biomass for anabolic processes that support cell proliferation. Expression levels of glucose transporters and rate-limiting enzymes regulate the rate of glycolytic flux. Intermediates that branch out from glycolysis are responsible for redox homeostasis, glycosylation, and biosynthesis. Beyond enhanced glycolytic flux, pancreatic cancer cells activate nutrient salvage pathways, which includes autophagy and micropinocytosis, from which the generated sugars, amino acids, and fatty acids are used to buffer the stresses induced by nutrient deprivation. Further, PDAC is characterized by extensive metabolic crosstalk between tumor cells and cells in the tumor microenvironment (TME). In this review, we will give an overview on recent progresses made in understanding glucose metabolism-related deregulations in PDAC.

scholarly journals Schwann cells support oncogenic potential of pancreatic cancer cells through TGFβ signaling

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Elodie Roger ◽  
Sylvie Martel ◽  
Adrien Bertrand-Chapel ◽  
Arnaud Depollier ◽  
Nicolas Chuvin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Schwann Cells ◽  
Stromal Cells ◽  
Transforming Growth Factor ◽  
Nerve Fibers ◽  
Dependent Manner ◽  
Tgfβ Signaling ◽  
Pancreatic Cancer Cells ◽  
Neural Remodeling

AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the solid tumors with the poorest prognosis. The stroma of this tumor is abundant and composed of extracellular matrix and stromal cells (including cancer-associated fibroblasts and immune cells). Nerve fibers invading this stroma represent a hallmark of PDAC, involved in neural remodeling, which participates in neuropathic pain, cancer cell dissemination and tumor relapse after surgery. Pancreatic cancer-associated neural remodeling is regulated through functional interplays mediated by physical and molecular interactions between cancer cells, nerve cells and surrounding Schwann cells, and other stromal cells. In the present study, we show that Schwann cells (glial cells supporting peripheral neurons) can enhance aggressiveness (migration, invasion, tumorigenicity) of pancreatic cancer cells in a transforming growth factor beta (TGFβ)-dependent manner. Indeed, we reveal that conditioned medium from Schwann cells contains high amounts of TGFβ able to activate the TGFβ-SMAD signaling pathway in cancer cells. We also observed in human PDAC samples that high levels of TGFβ signaling activation were positively correlated with perineural invasion. Secretome analyses by mass spectrometry of Schwann cells and pancreatic cancer cells cultured alone or in combination highlighted the central role of TGFβ in neuro-epithelial interactions, as illustrated by proteomic signatures related to cell adhesion and motility. Altogether, these results demonstrate that Schwann cells are a meaningful source of TGFβ in PDAC, which plays a crucial role in the acquisition of aggressive properties by pancreatic cancer cells.

Activation of glucagon-like peptide-1 receptor inhibits growth and promotes apoptosis of human pancreatic cancer cells in a cAMP-dependent manner

2014 ◽  
Vol 306 (12) ◽  
pp. E1431-E1441 ◽  
Author(s):  
Hejun Zhao ◽  
Rui Wei ◽  
Liang Wang ◽  
Qing Tian ◽  
Ming Tao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Human Pancreatic Cancer ◽  
Dependent Manner ◽  
Pancreatic Cancer Cells ◽  
Tumor Tissues ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) promotes pancreatic β-cell regeneration through GLP-1 receptor (GLP-1R) activation. However, whether it promotes exocrine pancreas growth and thereby increases the risk of pancreatic cancer has been a topic of debate in recent years. Clinical data and animal studies published so far have been controversial. In the present study, we report that GLP-1R activation with liraglutide inhibited growth and promoted apoptosis in human pancreatic cancer cell lines in vitro and attenuated pancreatic tumor growth in a mouse xenograft model in vivo. These effects of liraglutide were mediated through activation of cAMP production and consequent inhibition of Akt and ERK1/2 signaling pathways in a GLP-1R-dependent manner. Moreover, we examined GLP-1R expression in human pancreatic cancer tissues and found that 43.3% of tumor tissues were GLP-1R-null. In the GLP-1R-positive tumor tissues (56.7%), the level of GLP-1R was lower compared with that in tumor-adjacent normal pancreatic tissues. Furthermore, the GLP-1R-positive tumors were significantly smaller than the GLP-1R-null tumors. Our study shows for the first time that GLP-1R activation has a cytoreductive effect on human pancreatic cancer cells in vitro and in vivo, which may help address safety concerns of GLP-1-based therapies in the context of human pancreatic cancer.

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