Pancreatic Cancer Resistance to TRAIL Therapy: Regulators of the Death Inducing Signaling Complex

2015 ◽  
pp. 235-265
Author(s):  
Yabing Chen ◽  
Kaiyu Yuan ◽  
Jay McDonald
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Resistance ◽  
Signaling Complex

scholarly journals MiR-331-3p Links to Drug Resistance of Pancreatic Cancer Cells by Activating WNT/β-Catenin Signal via ST7L

2020 ◽  
Vol 19 ◽  
pp. 153303382094580
Author(s):  
Ting Zhan ◽  
Xiaoli Chen ◽  
Xia Tian ◽  
Zheng Han ◽  
Meng Liu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Drug Resistance ◽  
Multidrug Resistance ◽  
Cancer Cells ◽  
Breast Cancer Resistance Protein ◽  
Cancer Resistance ◽  
Multidrug Resistance Protein 1 ◽  
Pancreatic Cancer Cells ◽  
Resistance Protein ◽  
Multidrug Resistance Related Protein

Background: Pancreatic cancer is an aggressive type of cancer with poor prognosis, short survival rate, and high mortality. Drug resistance is a major cause of treatment failure in the disease. MiR-331-3p has been reported to play an important role in several cancers. We previously showed that miR-331-3p is upregulated in pancreatic cancer and promotes pancreatic cancer cell proliferation and epithelial-to-mesenchymal transition–mediated metastasis by targeting ST7L. However, it is uncertain whether miR-331-3p is involved in drug resistance. Methods: We investigated the relationship between miR-331-3p and pancreatic cancer drug resistance. As part of this, microRNA mimics or inhibitors were transfected into pancreatic cancer cells. Quantitative polymerase chain reaction was used to detect miR-331-3p expression, and flow cytometry was used to detect cell apoptosis. The Cell Counting Kit-8 assay was used to measure the IC50 values of gemcitabine in pancreatic cancer cells. The expression of multidrug resistance protein 1, multidrug resistance-related protein 1, breast cancer resistance protein, β-Catenin, c-Myc, Cyclin D1, Bcl-2, and Caspase-3 was evaluated by Western blotting. Results: We confirmed that miR-331-3p is upregulated in gemcitabine-treated pancreatic cancer cells and plasma from chemotherapy patients. We also confirmed that miR-331-3p inhibition decreased drug resistance by regulating cell apoptosis and multidrug resistance protein 1, multidrug resistance-related protein 1, and breast cancer resistance protein expression in pancreatic cancer cells, whereas miR-331-3p overexpression had the opposite effect. We further demonstrated that miR-331-3p effects in drug resistance were partially reversed by ST7L overexpression. In addition, overexpression of miR-331-3p activated Wnt/β-catenin signaling in pancreatic cancer cells, and ST7L overexpression restored activation of Wnt/β-catenin signaling. Conclusions: Taken together, our data demonstrate that miR-331-3p contributes to drug resistance by activating Wnt/β-catenin signaling via ST7L in pancreatic cancer cells. These data provide a theoretical basis for new targeted therapies in the future.

scholarly journals Pancreatic cancer resistance conferred by stellate cells: looking for new preclinical models

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Pei Pei Che ◽  
Alessandro Gregori ◽  
Omidreza Firuzi ◽  
Max Dahele ◽  
Peter Sminia ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stellate Cells ◽  
Cancer Resistance ◽  
Preclinical Models

Abstract 4977: MIR1307 mediates pancreatic cancer resistance to FOLFIRINOX chemotherapy by affecting response to DNA damage

2018 ◽  
Author(s):  
Pietro Carotenuto ◽  
Domenico Zito ◽  
Maria C. Previdi ◽  
Maya Raj ◽  
Matteo Fassan ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Dna Damage ◽  
Cancer Resistance

scholarly journals Hexosamine pathway inhibition overcomes pancreatic cancer resistance to gemcitabine through unfolded protein response and EGFR-Akt pathway modulation

Oncogene ◽  
2020 ◽  
Vol 39 (20) ◽  
pp. 4103-4117
Author(s):  
Francesca Ricciardiello ◽  
Yang Gang ◽  
Roberta Palorini ◽  
Quanxiao Li ◽  
Marco Giampà ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Unfolded Protein Response ◽  
Akt Pathway ◽  
Cancer Resistance ◽  
Unfolded Protein ◽  
Hexosamine Pathway ◽  
Pathway Inhibition ◽  
Protein Response

scholarly journals The long non-coding RNA HOTAIR enhances pancreatic cancer resistance to TNF-related apoptosis-inducing ligand

2017 ◽  
Vol 292 (25) ◽  
pp. 10390-10397 ◽  
Author(s):  
Shan-zhong Yang ◽  
Fei Xu ◽  
Tong Zhou ◽  
Xinyang Zhao ◽  
Jay M. McDonald ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Resistance ◽  
Non Coding Rna ◽  
Long Non Coding Rna

scholarly journals Inclusion of cancer-associated fibroblasts in drug screening assays to evaluate pancreatic cancer resistance to therapeutic drugs

2021 ◽  
Author(s):  
Sarah Brumskill ◽  
Lawrence N. Barrera ◽  
Peter Calcraft ◽  
Caroline Phillips ◽  
Eithne Costello
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
3D Models ◽  
In Vitro Models ◽  
Ductal Adenocarcinoma ◽  
Cancer Associated Fibroblasts ◽  
Cancer Resistance ◽  
Pancreatic Cell ◽  
Chemotherapy Drugs

AbstractPancreatic ductal adenocarcinoma (PDAC) is characterised by a pro-inflammatory stroma and multi-faceted microenvironment that promotes and maintains tumorigenesis. However, the models used to test new and emerging therapies for PDAC have not increased in complexity to keep pace with our understanding of the human disease. Promising therapies that pass pre-clinical testing often fail in pancreatic cancer clinical trials. The objective of this study was to investigate whether changes in the drug-dosing regimen or the addition of cancer-associated fibroblasts (CAFs) to current existing models can impact the efficacy of chemotherapy drugs used in the clinic. Here, we reveal that gemcitabine and paclitaxel markedly reduce the viability of pancreatic cell lines, but not CAFs, when cultured in 2D. Following the use of an in vitro drug pulsing experiment, PDAC cell lines showed sensitivity to gemcitabine and paclitaxel. However, CAFs were less sensitive to pulsing with gemcitabine compared to their response to paclitaxel. We also identify that a 3D co-culture model of MIA PaCa-2 or PANC-1 with CAFs showed an increased chemoresistance to gemcitabine when compared to standard 2D mono-cultures a difference to paclitaxel which showed no measurable difference between the 2D and 3D models, suggesting a complex interaction between the drug in study and the cell type used. Changes to standard 2D mono-culture-based assays and implementation of 3D co-culture assays lend complexity to established models and could provide tools for identifying therapies that will match clinically the success observed with in vitro models, thereby aiding in the discovery of novel therapies.

scholarly journals Exosomal lncRNA UCA1 Derived From Pancreatic Stellate Cells Promotes Gemcitabine Resistance in Pancreatic Cancer via the SOCS3/EZH2 Axis

2021 ◽  
Vol 11 ◽  
Author(s):  
Yuan Chi ◽  
He Xin ◽  
Zhaoyu Liu
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Mtt Assay ◽  
Histone Methylation ◽  
Methylation Level ◽  
Stellate Cells ◽  
Pancreatic Stellate Cells ◽  
Gene Region ◽  
Cancer Resistance ◽  
Pancreatic Cancer Cells

ObjectivePancreatic cancer is associated with poor prognosis and dismal survival rates. This study aims to investigate roles of lncRNA UCA1-loaded exosomes secreted by pancreatic stellate cells (PSCs) in Gemcitabine (Gem) resistance of pancreatic cancer under hypoxia, which involves the methylation of SOCS3 and EZH2 recruitment.MethodsThe exosomes were isolated from PSCs and hypoxic PSCs (HPSCs), and co-cultured with pancreatic cancer cells transduced with manipulated lncRNA UCA1, EZH2, and SOCS3. The interaction among lncRNA UCA1, EZH2, and SOCS3 was characterized by RIP and ChIP assays. Next, MTT assay, flow cytometry and TUNEL staining and Transwell assay were used to detect cell viability, apoptosis, invasion, and migration. Gem-resistant pancreatic cancer cell line (GemMIA-R3) was established, which was applied in a mouse xenograft model of pancreatic cancer, with MTT assay to determine Gem sensitivity.ResultsLncRNA UCA1 was highly expressed, while SOCS3 was poorly expressed in pancreatic cancer tissues. Hypoxia induced activation of PSCs and promoted release of exosomes. LncRNA UCA1 delivered by hypoxic PSC-derived exosomes (HPSC-EXO) regulated histone methylation level in SOCS3 gene region through recruitment of EZH2. In vitro and in vivo experimental results confirmed that lncRNA UCA1-loaded HPSC-EXO promoted malignant phenotypes, inhibited apoptosis, and promoted Gem resistance of pancreatic cancer cells as well as tumorigenesis in mice.ConclusionUnder hypoxic conditions, exosomes secreted by hypoxia-induced PSCs deliver lncRNA UCA1 into pancreatic cancer cells, where lncRNA UCA1 recruits EZH2 and regulates histone methylation level in SOCS3 gene region, thereby augmenting pancreatic cancer resistance to Gem.

scholarly journals Pancreatic Cancer Meets Human Microbiota: Close Encounters of the Third Kind

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1231
Author(s):  
Tatjana Arsenijevic ◽  
Remy Nicolle ◽  
Christelle Bouchart ◽  
Nicky D’Haene ◽  
Pieter Demetter ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Human Microbiome ◽  
Predictive Biomarker ◽  
Ductal Adenocarcinoma ◽  
Cancer Resistance ◽  
First Line ◽  
Resistance To Therapy ◽  
Dismal Prognosis ◽  
Over 40 Years ◽  
Potential Use

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal types of cancer with a dismal prognosis. The five-year survival rate has not changed significantly in over 40 years. Current first-line treatments only offer a modest increase in overall survival in unselected populations, and there is an urgent need to personalize treatment in this aggressive disease and develop new therapeutic strategies. Evolving evidence suggests that the human microbiome impacts cancerogenesis and cancer resistance to therapy. The mechanism of action and interaction of microbiome and PDAC is still under investigation. Direct and indirect effects have been proposed, and the use of several microbiome signatures as predictive and prognostic biomarkers for pancreatic cancer are opening new therapeutic horizons. In this review, we provide an overview for the clinicians of studies describing the influence and associations of oral, gastrointestinal and intratumoral microbiota on PDAC development, progression and resistance to therapy and the potential use of microbiota as a diagnostic, prognostic and predictive biomarker for PDAC.

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