scholarly journals The Case for GNMT as a Biomarker and a Therapeutic Target in Pancreatic Cancer

2021 ◽  
Vol 14 (3) ◽  
pp. 209
Author(s):  
Zachary Heinzman ◽  
Connor Schmidt ◽  
Marek K. Sliwinski ◽  
Nalin C. W. Goonesekere
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
Therapeutic Target ◽  
Early Stage ◽  
Dependent Manner ◽  
Strong Inhibitor ◽  
Tissue Samples ◽  
Reverse Transcription Pcr ◽  
Tumor Stages ◽  
Early Tumor

The high mortality rate for pancreatic cancer (PC) is due to the lack of specific symptoms at early tumor stages and a high biological aggressiveness. Reliable biomarkers and new therapeutic targets would help to improve outlook in PC. In this study, we analyzed the expression of GNMT in a panel of pancreatic cancer cell lines and in early-stage paired patient tissue samples (normal and diseased) by quantitative reverse transcription-PCR (qRT-PCR). We also investigated the effect of 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranoside (PGG) as a therapeutic agent for PC. We find that GNMT is markedly downregulated (p < 0.05), in a majority of PC cell lines. Similar results are observed in early-stage patient tissue samples, where GNMT expression can be reduced by a 100-fold or more. We also show that PGG is a strong inhibitor of PC cell proliferation, with an IC50 value of 12 ng/mL, and PGG upregulates GNMT expression in a dose-dependent manner. In conclusion, our data show that GNMT has promise as a biomarker and as a therapeutic target for PC.

scholarly journals SUN-132 KLF5 Is a Poor Prognostic Marker and Therapeutic Target for Middle Eastern Papillary Thyroid Carcinoma

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Khawla S Al-Kuraya ◽  
Abdul K Siraj ◽  
Pratheeshkumar Poyil ◽  
Divya Padmaja ◽  
Sandeep Kumar Parvathareddy ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Cell Lines ◽  
Therapeutic Target ◽  
Critical Role ◽  
Dependent Manner ◽  
Papillary Thyroid ◽  
Inhibition Of Proliferation ◽  
Over Expression

Abstract Thyroid cancer is the second most common malignancy among females in Saudi Arabia, with Papillary thyroid carcinoma (PTC) accounting for 80-90%. The Kruppel-like factor 5 (Klf5) is a transcription factor that play a critical role in cell transformation, proliferation and oncogenesis. Immunohistochemical analysis of KLF5 was performed in 1219 PTC cases. KLF5 over-expression was noted in 65.1% (793/1219) of PTCs, and was significantly associated with tall-cell variant (p &lt;0.0001), extrathyroidal extension (p = 0.0003), lymph node metastasis (p &lt; 0.0001) and stage IV tumors (p &lt; 0.0001). Significant association was also noted with HIF-1α over-expression (p = 0.0492). Interestingly, KLF5 over-expressing tumors showed poor disease-free survival (p = 0.0066). Functional studies in PTC cell lines showed that KLF5 co-immunoprecipitated with HIF-1α. Knockdown of KLF5 decreased the expression of HIF-1α while KLF5 was not affected by HIF-1α inhibition, suggesting that KLF5 is a functional upstream of HIF-1α. Down-regulation of KLF5 using specific inhibitor, ML264 or siRNA inhibited cell invasion and migration. In addition, treatment of PTC cell lines with ML264 resulted in inhibition of proliferation and induction of apoptosis in a dose-dependent manner. Furthermore, silencing of KLF5 significantly decreased the self-renewal ability of spheroids generated from PTC cells. Our findings confer that KLF5 may be a potential therapeutic target for the treatment of papillary thyroid cancer.

A Serum Marker for Early Pancreatic Cancer with a Possible Link to Diabetes

2021 ◽  
Author(s):  
Hoonsik Nam ◽  
Sunmi Kang ◽  
Min Seok Park ◽  
Suyeon Kang ◽  
Han Sun Kim ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
Normal Cell ◽  
Diagnostic Performance ◽  
Early Stage ◽  
Serum Marker ◽  
Diabetic Patients ◽  
Diagnostic Biomarker ◽  
Diabetic Status ◽  
Validation Set

Abstract Background Pancreatic cancer (PC) has a grim prognosis, and an early diagnostic biomarker has been highly desired. The molecular link between diabetes and PC has not been well-established. Methods Bioinformatics screening was performed for a serum PC marker. Experiments in cell lines (5 PC and 1 normal cell lines), mouse models, and human tissue staining (37 PC and 10 normal cases) were performed to test asprosin production from PC. Asprosin’s diagnostic performance was tested with serums from multi-center cohorts (347 PC, 209 normal, and 55 additional diabetic subjects) and evaluated according to PC status, stages, and diabetic status, which was compared with that of CA19-9. Results Asprosin, a diabetes-related hormone, was found from the bioinformatics screening, and its production from PC was confirmed. Serum asprosin levels from multi-center cohorts yielded an age-adjusted diagnostic AUC of 0.987 (95% confidence interval [CI] = 0.961 to 0.997), superior to that of CA19-9 (AUC = 0.876, 95% CI = 0.847 to 0.905), and a cut-off of 7.18 ng/mL, at which the validation set exhibited a sensitivity of 0.957 and a specificity of 0.924. Importantly, the performance was maintained in early-stage and non-metastatic PC, consistent with the tissue staining. A slightly lower performance against additional diabetic patients (n = 55) was restored by combining asprosin and CA19-9 (AUC = 0.985, 95% CI = 0.975 to 0.995). Conclusion Asprosin is presented as an early-stage PC serum marker that may provide clues for PC-induced diabetes. Larger prospective clinical studies are warranted to solidify its utility.

scholarly journals Degalactotigonin, a Steroidal Glycoside from Solanum nigrum, Induces Apoptosis and Cell Cycle Arrest via Inhibiting the EGFR Signaling Pathways in Pancreatic Cancer Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Hoang Le Tuan Anh ◽  
Phuong Thao Tran ◽  
Do Thi Thao ◽  
Duong Thu Trang ◽  
Nguyen Hai Dang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pancreatic Cancer ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Solanum Nigrum ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Cycle Arrest

Degalactotigonin (1) and three other steroidal compounds solasodine (2), O-acetyl solasodine (3), and soladulcoside A (4) were isolated from the methanolic extract of Solanum nigrum, and their chemical structures were elucidated by spectroscopic analyses. The isolated compounds were evaluated for cytotoxic activity against human pancreatic cancer cell lines (PANC1 and MIA-PaCa2) and lung cancer cell lines (A549, NCI-H1975, and NCI-H1299). Only degalactotigonin (1) showed potent cytotoxicity against these cancer cell lines. Compound 1 induced apoptosis in PANC1 and A549 cells. Further study on its mechanism of action in PANC1 cells demonstrated that 1 significantly inhibited EGF-induced proliferation and migration in a concentration-dependent manner. Treatment of PANC1 cells with degalactotigonin induced cell cycle arrest at G0/G1 phase. Compound 1 induced downregulation of cyclin D1 and upregulation of p21 in a time- and concentration-dependent manner and inhibited EGF-induced phosphorylation of EGFR, as well as activation of EGFR downstream signaling molecules such as Akt and ERK.

scholarly journals Separation and Identification of HSP-Associated Protein Complexes from Pancreatic Cancer Cell Lines Using 2D CN/SDS-PAGE Coupled with Mass Spectrometry

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Zhiyun Zhao ◽  
Hui Liu ◽  
Xinli Wang ◽  
Xiaodong Wang ◽  
Zhili Li
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Protein Function ◽  
Pancreatic Cancer Cell ◽  
Protein Complexes ◽  
Early Stage ◽  
Cancer Cell Lines ◽  
Building Models ◽  
Sds Page

Protein complexes are a cornerstone of many biological processes and together they form various types of molecular machinery. A broad understanding of these protein complexes is crucial for revealing and building models of protein function and regulation. Pancreatic cancer is a highly lethal disease which is difficult to diagnose at early stage and even more difficult to cure. In this study, we applied a gradient clear native gel system combined with subsequent second-dimensional SDS-PAGE to separate protein complexes from cell lysates of SW1990 and PANC-1 pancreatic cancer cell lines with different degrees of differentiation. Ten heat-shock-protein- (HSP-) associated protein complexes were separated and identified, and the differentially expressed proteins related to cancers were also found, such as HSP60, protein disulfide-isomerase A4 (ERp72), and transitional endoplasmic reticulum ATPase (TER ATPase).

Atorvastatin to inhibit pancreatic cancer cells proliferation and invasion via suppression neurotrophin receptor signaling.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15725-e15725
Author(s):  
Shengjun Ji
Keyword(s):  
Pancreatic Cancer ◽  
Western Blot ◽  
Cancer Cells ◽  
Cell Lines ◽  
Medical Center ◽  
Neurotrophin Receptor ◽  
Dependent Manner ◽  
Receptor Signaling ◽  
Pancreatic Cancer Cells ◽  
Trk A

e15725 Background: Pancreatic cancer is an uncommon but fatal malignant tumor, only 20% of which show any significant response to chemo-radiotherapy. Tumor metabolism research revealed that pancreatic cancer cells highly dependent on cholesterol uptake. So, in the present study, we have determined the effectiveness of atorvastatin, one drug originally used to lower cholesterol, against pancreatic carcinogenesis in various pancreatic cancer cell lines. Methods: To investigate atorvastatin effects in pancreatic cancer cells, two cell lines (PANC-1 and SW1990) were treated with different atorvastatin doses. The anti-proliferative, apoptotic and anti-invasive properties of atorvastatin were evaluated using MTS, cytoplasmic histone-DNA fragmentation and matrigel invasive assays, respectively. And western blot was used to evaluate the neurotrophin receptor signaling of NGF/Trk A, BDNF/TrkB and NT3/Trk C. Results: Atorvastatin suppressed pancreatic cancer cells proliferation, clone formation and invasion in a dose-dependent manner. The dose of atorvastatin at 10^-5mmol/L would be able to achieve obvious anti-tumor effect in vitro. Cell-cycle analysis demonstrated that cells were arrested in the S phase. Western blot showed increased protein expression of cleaved caspase-3, caspase-9, p21, p-chk2 and decrease in protein level of NGF/Trk A and NT3/Trk C. Conclusions: The current results demonstrated the anti-tumor effects of atorvastatin on pancreatic cancer cells, providing initial evidence towards its potential therapeutic use. Acknowledgment:This study was supported by Suzhou Cancer Clinical Medical Center Szzx201506.

Design, Synthesis, and Biological Evaluation of 4-amino Substituted 2Hchromen- 2-one Derivatives as an NEDD8 Activating Enzyme Inhibitor in Pancreatic Cancer Cells

2020 ◽  
Vol 16 (7) ◽  
pp. 969-983
Author(s):  
Lijuan Zhu ◽  
Peng Lu ◽  
Lei Gong ◽  
Cheng Lu ◽  
Mengli Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Synergistic Effect ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Biological Evaluation ◽  
Human Pancreatic Cancer ◽  
Dependent Manner ◽  
Pancreatic Cancer Cells ◽  
Compound 21

Background: NEDD8 activating enzyme (NAE) plays a critical role in various cellular functions in carcinomas. The selective inhibition of NAE could mediate the rate of ubiquitination and the subsequent degradation of proteins associated with cancer so as to achieve the purpose of treatment. Objective: In this article, we decided to study the synthesis and screening of 4-amino substituted 2H-chromen-2-one derivatives against cancer cell lines, specifically the human pancreatic cancer cell line BxPC-3. Methods: After synthesis of twenty targeted compounds, we evaluated their anti-proliferative activity against six cancer cell lines, cytotoxicity against three normal cell lines through MTT assay, and hemolysis to screen out the candidate compound, which was further conducted drug-like physical property measurement, target confirmation by enzyme-based experiment, cell apoptosis, and synergistic effect research. Results: Starting from intermediates 4 and 5, several new 4-amino substituted 2H-chromen-2-one derivatives (9-28) were synthesized and evaluated for their cell activities using six cancer cell lines. We performed tests of cytotoxicity, hemolysis, ATP-dependent NAE inhibition in the enzyme- based system, apoptosis, and synergistic effect in BxPC-3 cells against the best candidate compound 21. Conclusion: Based on these results, we found that compound 21 inhibited NAE activity in an ATP-dependent manner in the enzyme-based system, induced apoptosis in BxPC-3 cells, and synergized with bortezomib on BxPC-3 cell growth inhibition. Additionally, it had low toxicity with reasonable Log P-value and water solubility.

scholarly journals The antagonistic regulation of human MUC4 and ErbB-2 genes by the Ets protein PEA3 in pancreatic cancer cells: implications for the proliferation/differentiation balance in the cells

2005 ◽  
Vol 386 (1) ◽  
pp. 35-45 ◽  
Author(s):  
Valérie FAUQUETTE ◽  
Michael PERRAIS ◽  
Sylvain CERULIS ◽  
Nicolas JONCKHEERE ◽  
Marie-Paule DUCOUROUBLE ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Biological Marker ◽  
Proximal Region ◽  
Site Directed Mutagenesis ◽  
Tyrosine Kinase Receptor ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Pancreatic Cancer Cells

The human transmembrane mucin MUC4 is aberrantly expressed in 75% of pancreatic ductal adenocarcinomas, whereas no expression is found in normal pancreas. Therefore MUC4 appears as a useful biological marker for the diagnosis of ductal adenocarcinomas. Since rat Muc4 was shown to interact with ErbB-2 tyrosine kinase receptor and to either promote cell survival and differentiation or cell proliferation, it is postulated that MUC4 may also participate in pancreatic carcinogenesis. Our aim was to investigate in parallel the role of the Ets factor PEA3 in MUC4 and ErbB-2 transcriptional regulation in pancreatic cancer cells. Two MUC4-expressing WD (well-differentiated) (CAPAN-1 and -2) and one MUC4-non-expressing poorly differentiated (PANC-1) cell lines were used. The three cell lines express ErbB-2 at different levels. By co-transfection and site-directed mutagenesis, we show that PEA3 is a transactivator of the MUC4 promoter and that the −216 and −2368 PEA3 binding sites of the MUC4 promoter are essential. We also demonstrate that PEA3 acts in synergy with c-Jun and specificity protein 1 to transactivate the proximal region of the MUC4 promoter and increase MUC4 mRNA levels in WD cells. These results suggest that MUC4 is a new target gene of the Ets factor PEA3 in pancreatic cancer cells. In contrast, PEA3 represses the transcriptional activity of two fragments of the ErbB-2 promoter in a dose-dependent manner and decreases the endogenous ErbB-2 mRNA levels in WD cell lines. Thus, PEA3, by its capacity to up-regulate the epithelial marker MUC4 and to down-regulate the ErbB-2 oncogene, appears as a key regulator of the differentiation/proliferation balance in pancreatic cancer cells.

Differential Expression of Metastasis-Associated Genes in Papilla of Vater and Pancreatic Cancer Correlates With Disease Stage

2001 ◽  
Vol 19 (9) ◽  
pp. 2422-2432 ◽  
Author(s):  
Helmut Friess ◽  
Xiao-Zhong Guo ◽  
Adrien A. Tempia-Caliera ◽  
Akira Fukuda ◽  
Marcus E. Martignoni ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
In Situ Hybridization ◽  
Early Stage ◽  
Expression Patterns ◽  
Tumor Biology ◽  
Disease Stage ◽  
Papilla Of Vater ◽  
Advanced Tumor ◽  
Tumor Stages

PURPOSE: Papilla of Vater cancer has a much better prognosis than pancreatic cancer. It is not known whether this is the result of differences in the tumor biology of the two malignancies. Because metastasis formation is a critical step in tumor progression and a negative prognostic factor, we compared the expression of nm23-H1 and KAI1, two metastasis-suppressing genes, in papilla of Vater cancer and pancreatic cancer. PATIENTS AND METHODS: Analysis was performed in nine normal human papilla of Vater samples, 27 papilla of Vater cancers, 16 normal pancreatic samples, and 29 pancreatic cancers. Expression of nm23-H1 and KAI1 was analyzed by Northern blot analysis and in situ hybridization. In addition, immunohistochemistry was performed to localize the respective proteins. RESULTS: There was no difference in nm23-H1 and KAI1 mRNA expression levels in normal versus cancerous papilla of Vater samples. In contrast, nm23-H1 and KAI1 RNA expression was upregulated in early tumor stages of pancreatic cancer and reduced in advanced tumor stages. When expression of nm23-H1 and KAI1 RNA was analyzed by use of in situ hybridization, normal epithelial cells of the papilla of Vater exhibited mRNA staining intensity similar to that of papilla of Vater cancer cells. Similar levels of nm23-H1 and KAI1 immunoreactivity also were observed in these samples. In contrast, early stage pancreatic cancer samples exhibited stronger nm23-H1 and KAI1 immunoreactivity than normal controls. Furthermore, early pancreatic cancer stages exhibited higher KAI1 and nm23-H1 immunostaining than advanced tumor stages. CONCLUSION: Differences in the expression patterns of the two tumor suppressor genes nm23-H1 and KAI1 may contribute to the different prognoses of papilla of Vater cancer and pancreatic cancer. Our findings support the hypothesis that biologic differences rather than earlier diagnosis influence the different outcomes of these two tumor entities.

scholarly journals miR-9-5p Exerts a Dual Role in Cervical Cancer and Targets Transcription Factor TWIST1

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 65 ◽  
Author(s):  
Iris Babion ◽  
Annelieke Jaspers ◽  
Annina P. van Splunter ◽  
Iris A.E. van der Hoorn ◽  
Saskia M. Wilting ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Transcription Factor ◽  
Cell Lines ◽  
Epithelial To Mesenchymal Transition ◽  
Dual Role ◽  
Dependent Manner ◽  
Tissue Samples ◽  
Mesenchymal Transition ◽  
High Risk Hpv ◽  
Hrhpv Type

Squamous cell carcinoma (SCC) and adenocarcinoma (AC) represent the major cervical cancer histotypes. Both histotypes are caused by infection with high-risk HPV (hrHPV) and are associated with deregulated microRNA expression. Histotype-dependent expression has been observed for miR-9-5p, showing increased expression in SCC and low expression in AC. Here, we studied the regulation and functionality of miR-9-5p in cervical SCCs and ACs using cervical tissue samples and hrHPV-containing cell lines. Expression and methylation analysis of cervical tissues revealed that low levels of miR-9-5p in ACs are linked to methylation of its precursor genes, particularly miR-9-1. Stratification of tissue samples and hrHPV-containing cell lines suggested that miR-9-5p depends on both histotype and hrHPV type, with higher expression in SCCs and HPV16-positive cells. MiR-9-5p promoted cell viability and anchorage independence in cervical cancer cell lines SiHa (SCC, HPV16) and CaSki (metastasized SCC, HPV16), while it played a tumor suppressive role in HeLa (AC, HPV18). TWIST1, a transcription factor involved in epithelial-to-mesenchymal transition (EMT), was established as a novel miR-9-5p target. Our results show that miR-9-5p plays a dual role in cervical cancer in a histotype- and hrHPV type-dependent manner. MiR-9-5p mediated silencing of TWIST1 suggests two distinct mechanisms towards EMT in cervical cancer.

scholarly journals MicroRNA-126 enhances the biological function of endothelial progenitor cells under oxidative stress via PI3K/Akt/GSK-3β and ERK1/2 signaling pathways

2020 ◽  
Author(s):  
Qinqin Wu ◽  
Benling Qi ◽  
Xiaoyu Duan ◽  
Xiaoyan Ming ◽  
Fengqin Yan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Biological Function ◽  
Glycogen Synthase ◽  
Early Stage ◽  
Tube Formation ◽  
Dependent Manner ◽  
Endothelial Progenitor ◽  
H2o2 Treatment ◽  
Reverse Transcription Pcr ◽  
Gsk 3Β

Endothelial progenitor cell (EPC) transplantation is a safe and effective method to treat acute myocardial infarction (AMI). However, oxidative stress leads to the death of a large number of EPCs in the early stage of transplantation, severely weakening the therapeutic effect. Previous studies demonstrated that microRNAs (miRNAs) regulate the biological function of EPCs. The aim of the current study was to investigate the effect of miRNA on the biological function of EPCs under oxidative stress. Quantitative reverse transcription PCR was performed to detect the expression of miR-126, miR-508-5p, miR-150, and miR-16 in EPCs from rats, among which miR-126 showed a relatively higher expression. Treatment with H2O2 decreased miR-126 expression in EPCs in a dose-dependent manner. EPCs were further transfected with miR-126 mimics or inhibitors, followed by H2O2 treatment. Overexpression of miR-126 enhanced the proliferation, migration, and tube formation of H2O2-treated EPCs. MiR-126 overexpression also inhibited reactive oxygen species and malondialdehyde levels and enhanced superoxide dismutase levels, as well as increased angiopoietin (Ang)1 expression and decreased Ang2 expression in H2O2-treated EPCs. Moreover, miR-126 participated in the regulation of phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (Akt)/ glycogen synthase kinase-3β (GSK-3β) and extracellular signal-regulated kinase (ERK)1/2 signaling in EPCs, where both pathways were activated after miR-126 overexpression in H2O2-treated EPCs. Overall, we showed that miR-126 promoted the biological function of EPCs under H2O2-induced oxidative stress by activating the PI3K/Akt/GSK-3β and ERK1/2 signaling pathway, which may serve as a new therapeutic approach to treat AMI.

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