scholarly journals NRF2 Knockdown Resensitizes 5-Fluorouracil-Resistant Pancreatic Cancer Cells by Suppressing HO-1 and ABCG2 Expression

2020 ◽  
Vol 21 (13) ◽  
pp. 4646
Author(s):  
Eui Joo Kim ◽  
Yoon Jae Kim ◽  
Hye In Lee ◽  
Seok-Hoo Jeong ◽  
Hyo Jung Nam ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Ductal Adenocarcinoma ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells ◽  
Emt Markers ◽  
Superoxide Dismutase 2

Chemoresistance is a leading cause of morbidity and mortality in patients with pancreatic cancer and remains an obstacle to successful treatment. The antioxidant transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (NRF2), which plays important roles in tumor angiogenesis and invasiveness, is upregulated in pancreatic ductal adenocarcinoma (PDAC), where it correlates with poor survival. Here, we investigated the role of NRF2 in two 5-Fluourouracil-resistant (5-FUR) PDAC cell lines: BxPC-3 and CFPAC-1. Levels of NRF2 and antioxidants, such as heme oxygenase 1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), and superoxide dismutase 2 (SOD2), were higher in the chemoresistant cells than in their chemosensitive counterparts. Expression of epithelial mesenchymal transition (EMT) markers, stemness markers, including Nanog, Oct4, and CD133, and that of the drug transporter ATP binding cassette, subfamily G, member A2 (ABCG2) was also upregulated in 5-FUR PDAC cells. NRF2 knockdown reversed 5-FU resistance of PDAC cells via suppression of ABCG2 and HO-1. In summary, these data indicate that NRF2 is a potential target for resensitizing 5-FUR PDAC cells to 5-FU to improve treatment outcomes in patients with pancreatic cancer.

scholarly journals Wnt/β-Catenin Signaling: The Culprit in Pancreatic Carcinogenesis and Therapeutic Resistance

2019 ◽  
Vol 20 (17) ◽  
pp. 4242 ◽  
Author(s):  
Monish Ram Makena ◽  
Himavanth Gatla ◽  
Dattesh Verlekar ◽  
Sahithi Sukhavasi ◽  
Manoj K. Pandey ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Cycle Progression ◽  
Patient Survival ◽  
Epithelial Mesenchymal Transition ◽  
Ductal Adenocarcinoma ◽  
Steady Increase ◽  
Mesenchymal Transition ◽  
Pancreatic Carcinogenesis ◽  
Tumor Immune Microenvironment

Pancreatic ductal adenocarcinoma (PDAC) is responsible for 7.3% of all cancer deaths. Even though there is a steady increase in patient survival for most cancers over the decades, the patient survival rate for pancreatic cancer remains low with current therapeutic strategies. The Wnt/β-catenin pathway controls the maintenance of somatic stem cells in many tissues and organs and is implicated in pancreatic carcinogenesis by regulating cell cycle progression, apoptosis, epithelial-mesenchymal transition (EMT), angiogenesis, stemness, tumor immune microenvironment, etc. Further, dysregulated Wnt has been shown to cause drug resistance in pancreatic cancer. Although different Wnt antagonists are effective in pancreatic patients, limitations remain that must be overcome to increase the survival benefits associated with this emerging therapy. In this review, we have summarized the role of Wnt signaling in pancreatic cancer and suggested future directions to enhance the survival of pancreatic cancer patients.

scholarly journals TGFβ Drives Metabolic Perturbations during Epithelial Mesenchymal Transition in Pancreatic Cancer: TGFβ Induced EMT in PDAC

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6204
Author(s):  
Meena U. Rajagopal ◽  
Shivani Bansal ◽  
Prabhjit Kaur ◽  
Shreyans K. Jain ◽  
Tatiana Altadil ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
High Resolution Mass Spectrometry ◽  
Ductal Adenocarcinoma ◽  
Resectable Pancreatic Cancer ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy wherein a majority of patients present metastatic disease at diagnosis. Although the role of epithelial to mesenchymal transition (EMT), mediated by transforming growth factor beta (TGFβ), in imparting an aggressive phenotype to PDAC is well documented, the underlying biochemical pathway perturbations driving this behaviour have not been elucidated. We used high-resolution mass spectrometry (HRMS) based molecular phenotyping approach in order to delineate metabolic changes concomitant to TGFβ-induced EMT in pancreatic cancer cells. Strikingly, we observed robust changes in amino acid and energy metabolism that may contribute to tumor invasion and metastasis. Somewhat unexpectedly, TGFβ treatment resulted in an increase in intracellular levels of retinoic acid (RA) that in turn resulted in increased levels of extracellular matrix (ECM) proteins including fibronectin (FN) and collagen (COL1). These findings were further validated in plasma samples obtained from patients with resectable pancreatic cancer. Taken together, these observations provide novel insights into small molecule dysregulation that triggers a molecular cascade resulting in increased EMT-like changes in pancreatic cancer cells, a paradigm that can be potentially targeted for better clinical outcomes.

scholarly journals Pancreatic cancer SLUGged

2020 ◽  
Vol 217 (9) ◽  
Author(s):  
Rachel H. Josselsohn ◽  
David A. Tuveson
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Nutrient Stress ◽  
Nutrient Sensing ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

In this issue of JEM, Recouvreux et al. (https://doi.org/10.1084/jem.20200388) describe the role of nutrient sensing in the induction of epithelial–mesenchymal transition. Glutamine-deficient pancreatic cancer cells up-regulate classic EMT regulator Slug, providing a link between nutrient stress and metastasis.

scholarly journals Coupling G2/M arrest to the Wnt/β-catenin pathway restrains pancreatic adenocarcinoma

2014 ◽  
Vol 21 (1) ◽  
pp. 113-125 ◽  
Author(s):  
Sayantani Sarkar ◽  
Chandan Mandal ◽  
Rajender Sangwan ◽  
Chitra Mandal
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Adenocarcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Underlying Mechanism ◽  
Ductal Adenocarcinoma ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells ◽  
Mutational Status ◽  
M Phase ◽  
Induced Apoptosis

β-catenin plays a pivotal role in organogenesis and oncogenesis. Alterations in β-catenin expression are common in pancreatic cancer, which is an extremely aggressive malignancy with a notably poor prognosis. In this report, we analyzed the apoptotic activity of withanolide-D (witha-D), a steroidal lactone that was purified from an Indian medicinal plant,Withania somnifera, and its underlying mechanism of action. Witha-D induced apoptosis in pancreatic ductal adenocarcinoma cells by prompting cell-cycle arrest at the G2/M phase. This lactone abrogated β-catenin signaling in these cells regardless of disease grade, mutational status, and gemcitabine sensitivity. Witha-D also upregulated E-cadherin in most cells, thereby supporting the inversion of the epithelial–mesenchymal transition. Furthermore, the Akt/Gsk3β kinase cascade was identified as a critical mediator of G2/M regulation and β-catenin signaling. Witha-D deactivated Akt, which failed to promote Gsk3β deactivation phosphorylation. Consequently, activated Gsk3β facilitated β-catenin destruction in pancreatic carcinoma cells. The knockdown of Chk1 and Chk2 further activated Akt and reversed the molecular signal. Taken together, the results of the current study represent the first evidence of β-catenin signal crosstalk during the G2/M phase by functionally inactivating Akt via witha-D treatment in pancreatic cancer cells. In conclusion, this finding suggests the potential identification of a new lead molecule in the treatment of pancreatic adenocarcinoma.

scholarly journals The role of long noncoding RNA AL161431.1 in the development and progression of pancreatic cancer

2021 ◽  
Author(s):  
Gang Ma ◽  
Guichen Li ◽  
Wufeng Fan ◽  
Yuanhong Xu ◽  
Shaowei Song ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Epithelial Mesenchymal Transition ◽  
Clinical Samples ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

Abstract Pancreatic cancer is known for its notorious fast progression and poor prognosis. Long noncoding RNA (lncRNA) AL161431.1 has been reported to be involved in the pathogenesis of different cancers. In this study, we explored the role of lncRNA AL161431.1 in the development and progression of pancreatic cancer by bioinformatic analysis, in vitro and in vivo experiments in pancreatic cancer BxPC-3 and SW1990 cells, as well as clinical samples. We found that lncRNA AL161431.1 was highly expressed in pancreatic cancer cells and tissues. Knock down of lncRNA AL161431.1 led to increased cancer cell death and cell cycle arrest. Xenograft growth of SW1990 cells with stable knockdown of lncRNA AL161431.1 in mice was significantly slower than that of SW1990 cells with scrambled control shRNA. Finally, we showed the involvement of lncRNA AL161431.1 in pancreatic cancer was related to its promotion of epithelial mesenchymal transition process.

scholarly journals The Role of Long Noncoding RNA AL161431.1 in the Development and Progression of Pancreatic Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Gang Ma ◽  
Guichen Li ◽  
Wufeng Fan ◽  
Yuanhong Xu ◽  
Shaowei Song ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Epithelial Mesenchymal Transition ◽  
Clinical Samples ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

Pancreatic cancer is known for its notorious fast progression and poor prognosis. Long noncoding RNA (lncRNA) AL161431.1 has been reported to be involved in the pathogenesis of different cancers. In this study, we explored the role of lncRNA AL161431.1 in the development and progression of pancreatic cancer by bioinformatic analysis, in vitro and in vivo experiments in pancreatic cancer BxPC-3 and SW1990 cells, as well as clinical samples. We found that lncRNA AL161431.1 was highly expressed in pancreatic cancer cells and tissues. Knock down of lncRNA AL161431.1 led to increased cancer cell death and cell cycle arrest. Xenograft growth of SW1990 cells with stable knockdown of lncRNA AL161431.1 in mice was significantly slower than that of SW1990 cells with scrambled control shRNA. Finally, we showed the involvement of lncRNA AL161431.1 in pancreatic cancer was related to its promotion of epithelial mesenchymal transition process.

scholarly journals Tumor-derived exosomal long noncoding RNA LINC01133, regulated by Periostin, contributes to pancreatic ductal adenocarcinoma epithelial-mesenchymal transition through the Wnt/β-catenin pathway by silencing AXIN2

Oncogene ◽  
2021 ◽  
Vol 40 (17) ◽  
pp. 3164-3179
Author(s):  
Yang Liu ◽  
Tianchi Tang ◽  
Xiaosheng Yang ◽  
Peng Qin ◽  
Pusen Wang ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Noncoding Rna ◽  
Pancreatic Tumor ◽  
Epithelial Mesenchymal Transition ◽  
Noncoding Rnas ◽  
Ductal Adenocarcinoma ◽  
Overall Survival Rate ◽  
Poor Overall Survival ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies and rapidly progressive diseases. Exosomes and long noncoding RNAs (lncRNAs) are emerging as vital mediators in tumor cells and their microenvironment. However, the detailed roles and mechanisms of exosomal lncRNAs in PDAC progression remain unknown. Here, we aimed to clarify the clinical significance and mechanisms of exosomal lncRNA 01133 (LINC01133) in PDAC. We analyzed the expression of LINC01133 in PDAC and found that exosomal LINC01133 expression was high and positively correlated with higher TNM stage and poor overall survival rate of PDAC patients. Further research demonstrated that Periostin could increase exosome secretion and then enhance LINC01133 expression. In addition, Periostin increased p-EGFR, p-Erk, and c-myc expression, and c-myc could bind to the LINC01133 promoter region. These findings suggested that LINC01133 can be regulated by Periostin via EGFR pathway activity. We also observed that LINC01133 promoted the proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) of pancreatic cancer cells. We subsequently evaluated the effect of LINC01133 on the Wnt/β-catenin pathway and confirmed that LINC01133 can interact with Enhancer Of Zeste Homolog 2 (EZH2) and then promote H3K27 trimethylation. This can further silence AXIN2 and suppress GSK3 activity, ultimately activating β-catenin. Collectively, these data indicate that exosomal LINC01133 plays an important role in pancreatic tumor progression, and targeting LINC01133 may provide a potential treatment strategy for PDAC.

scholarly journals Pancreatic Cancers with High Grade Tumor Budding Exhibit Hallmarks of Diminished Anti-Tumor Immunity

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1090
Author(s):  
Hassan Sadozai ◽  
Animesh Acharjee ◽  
Thomas Gruber ◽  
Beat Gloor ◽  
Eva Karamitopoulou
Keyword(s):  
Gene Expression ◽  
Pancreatic Cancer ◽  
Disease Progression ◽  
Immune Escape ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Budding ◽  
Ductal Adenocarcinoma ◽  
Low Grade ◽  
High Grade ◽  
Mesenchymal Transition

Tumor budding is associated with epithelial-mesenchymal transition and diminished survival in a number of cancer types including pancreatic ductal adenocarcinoma (PDAC). In this study, we dissect the immune landscapes of patients with high grade versus low grade tumor budding to determine the features associated with immune escape and disease progression in pancreatic cancer. We performed immunohistochemistry-based quantification of tumor-infiltrating leukocytes and tumor bud assessment in a cohort of n = 111 PDAC patients in a tissue microarray (TMA) format. Patients were divided based on the ITBCC categories of tumor budding as Low Grade (LG: categories 1 and 2) and High Grade (HG: category 3). Tumor budding numbers and tumor budding grade demonstrated a significant association with diminished overall survival (OS). HG cases exhibit notably reduced densities of stromal (S) and intratumoral (IT) T cells. HG cases also display lower M1 macrophages (S) and increased M2 macrophages (IT). These findings were validated using gene expression data from TCGA. A published tumor budding gene signature demonstrated a significant association with diminished survival in PDAC patients in TCGA. Immune-related gene expression revealed an immunosuppressive TME in PDAC cases with high expression of the budding signature. Our findings highlight a number of immune features that permit an improved understanding of disease progression and EMT in pancreatic cancer.

Sign in / Sign up

Export Citation Format

Share Document