scholarly journals 5-epi-Sinuleptolide from Soft Corals of the Genus Sinularia Exerts Cytotoxic Effects on Pancreatic Cancer Cell Lines via the Inhibition of JAK2/STAT3, AKT, and ERK Activity

Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 6932
Author(s):  
Wan-Chi Tsai ◽  
Wen-Hung Wang ◽  
Bo-Cian Huang ◽  
Chiung-Yao Huang ◽  
Jyh-Horng Sheu
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Metastatic Potential ◽  
Ductal Adenocarcinoma ◽  
M Cell ◽  
Cytotoxic Effects ◽  
Pancreatic Cancer Cells ◽  
Erk Phosphorylation ◽  
Underlying Mechanisms ◽  
Induced Apoptosis

Pancreatic ductal adenocarcinoma is one of the most lethal malignancies: more than half of patients are diagnosed with a metastatic disease, which is associated with a five-year survival rate of only 3%. 5-epi-Sinuleptolide, a norditerpene isolated from Sinularia sp., has been demonstrated to possess cytotoxic activity against cancer cells. However, the cytotoxicity against pancreatic cancer cells and the related mechanisms are unknown. The aim of this study was to evaluate the anti-pancreatic cancer potential of 5-epi-sinuleptolide and to elucidate the underlying mechanisms. The inhibitory effects of 5-epi-sinuleptolide treatment on the proliferation of pancreatic cancer cells were determined and the results showed that 5-epi-sinuleptolide treatment inhibited cell proliferation, induced apoptosis and G2/M cell cycle arrest, and suppressed the invasion of pancreatic cancer cells. The results of western blotting further revealed that 5-epi-sinuleptolide could inhibit JAK2/STAT3, AKT, and ERK phosphorylation, which may account for the diverse cytotoxic effects of 5-epi-sinuleptolide. Taken together, our present investigation unveils a new therapeutic and anti-metastatic potential of 5-epi-sinuleptolide for pancreatic cancer treatment.

scholarly journals Mechanical stress in pancreatic cancer: Signaling pathway adaptation activates cytoskeletal remodeling and enhances cell migration

2021 ◽  
Author(s):  
Maria Kalli ◽  
Ruxuan Li ◽  
Gordon B Mills ◽  
Triantafyllos Stylianopoulos ◽  
Ioannis K Zervantonakis
Keyword(s):  
Pancreatic Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Mechanical Stress ◽  
Large Scale ◽  
Metastatic Potential ◽  
Pancreatic Tumors ◽  
Pancreatic Cancer Cells ◽  
Novel Approach ◽  
Underlying Mechanisms

New treatments for patients with advanced or metastatic pancreatic cancers are urgently needed due to their resistance to all current therapies. Current studies focus on alternative treatment approaches that target or normalize the abnormal microenvironment of pancreatic tumors, which among others, is responsible for elevated mechanical stress in the tumor interior. Nevertheless, the underlying mechanisms by which mechanical stress regulates pancreatic cancer metastatic potential remain elusive. Herein, we used a large-scale proteomic assay to profile mechanical stress-induced signaling cascades that drive the motility of pancreatic cancer cells. Proteomic analysis, together with selective protein inhibition and siRNA treatments, revealed that mechanical stress enhances cell migration through activation of the p38 MAPK/HSP27 and JNK/c-Jun signaling axes, and activation of the actin cytoskeleton remodelers: Rac1, cdc42, and Myosin II. Our results highlight targeting aberrant signaling in cancer cells that are adapted to the mechanical tumor microenvironment as a novel approach to effectively limit pancreatic cancer cell migration.

scholarly journals Molecular signatures of mu opioid receptor and somatostatin receptor 2 in pancreatic cancer

2016 ◽  
Vol 27 (22) ◽  
pp. 3659-3672 ◽  
Author(s):  
Raphael Jorand ◽  
Sunetra Biswas ◽  
Devin L. Wakefield ◽  
Steven J. Tobin ◽  
Ottavia Golfetto ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Opioid Receptor ◽  
Somatostatin Receptor ◽  
Metastatic Potential ◽  
Mu Opioid Receptor ◽  
Ductal Adenocarcinoma ◽  
Mu Opioid ◽  
Pancreatic Cancer Cells ◽  
Epithelial Marker

Pancreatic ductal adenocarcinoma (PDAC), a particularly aggressive malignancy, has been linked to atypical levels, certain mutations, and aberrant signaling of G-protein–coupled receptors (GPCRs). GPCRs have been challenging to target in cancer because they organize into complex networks in tumor cells. To dissect such networks with nanometer-scale precision, here we combine traditional biochemical approaches with superresolution microscopy methods. A novel interaction specific to PDAC is identified between mu opioid receptor (MOR) and somatostatin receptor 2 (SSTR2). Although MOR and SSTR2 did not colocalize in healthy pancreatic cells or matching healthy patient tissues, the pair did significantly colocalize in pancreatic cancer cells, multicellular tumor spheroids, and cancerous patient tissues. Moreover, this association in pancreatic cancer cells correlated with functional cross-talk and increased metastatic potential of cells. Coactivation of MOR and SSTR2 in PDAC cells led to increased expression of mesenchymal markers and decreased expression of an epithelial marker. Together these results suggest that the MOR-SSTR2 heteromer may constitute a novel therapeutic target for PDAC.

scholarly journals Progressively De-Differentiated Pancreatic Cancer Cells Shift from Glycolysis to Oxidative Metabolism and Gain a Quiescent Stem State

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1572 ◽  
Author(s):  
Giulia Ambrosini ◽  
Elisa Dalla Pozza ◽  
Giuseppina Fanelli ◽  
Claudia Di Carlo ◽  
Andrea Vettori ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Metastatic Potential ◽  
Ductal Adenocarcinoma ◽  
Live Cells ◽  
Quiescent State ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is typically characterized by high chemoresistance and metastatic spread, features mainly attributable to cancer stem cells (CSCs). It is of central interest the characterization of CSCs and, in particular, the study of their metabolic features in order to selectively identify their peculiarities for an efficient therapeutic approach. In this study, CSCs have been obtained by culturing different PDAC cell lines with a specific growth medium. Cells were characterized for the typical stem/mesenchymal properties at short-, medium-, and long-term culture. Metabolomics, proteomics, analysis of oxygen consumption rate in live cells, and the effect of the inhibition of lactate transporter on cell proliferation have been performed to delineate the metabolism of CSCs. We show that gradually de-differentiated pancreatic cancer cells progressively increase the expression of both stem and epithelial-to-mesenchymal transition markers, shift their metabolism from a glycolytic to an oxidative one, and lastly gain a quiescent state. These quiescent stem cells are characterized by high chemo-resistance, clonogenic ability, and metastatic potential. Re-differentiation reverts these features, re-activating their proliferative capacity and glycolytic metabolism, which generally correlates with high aggressiveness. These observations add an important piece of knowledge to the comprehension of the biology of CSCs, whose metabolic plasticity could be exploited for the generation of promising and selective therapeutic approaches for PDAC patients.

Panax Notoginseng Saponins Promote Cell Death and Chemosensitivity in Pancreatic Cancer through the Apoptosis and Autophagy Pathways

2020 ◽  
Vol 20 ◽  
Author(s):  
Li-Chao Yao ◽  
Lun Wu ◽  
Wei Wang ◽  
Lu-Lu Zhai ◽  
Lin Ye ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Panax Notoginseng ◽  
Panax Notoginseng Saponins ◽  
Transwell Assay ◽  
Pancreatic Cancer Cells ◽  
New Strategy ◽  
Induced Apoptosis ◽  
Promote Cell Death

Background:: Panax Notoginseng Saponins (PNS) is used as traditional Chinese medicine for ischemic stroke and cardiovascular disease, it has been proven to possess anticancer activity recently. Objective:: In this study, we aimed to explore the anticancer curative effect and potential mechanisms of PNS in pancreatic cancer cells. Methods:: Pancreatic cancer Miapaca2 and PANC-1 cells were treated with PNS and Gemcitabine (Gem), respectively. Then the cell viability was assessed by CCK-8 assay, cell proliferation was tested by colony formation assay and EdU cell proliferation assay, cell migration and invasiveness were tested by wound healing assay and transwell assay respectively, and cell apoptosis was detected by flow cytometry. Finally, we detected the expression levels of proteins related to migration, apoptosis and autophagy through Western blotting. Results:: PNS not only inhibited the proliferation, migration, invasion and autophagy of Miapaca2 and PANC-1 cells, but also induced apoptosis and promoted chemosensitivity of pancreatic cancer cells to Gem. Conclusion:: PNS may exhibit cytotoxicity and increase chemosensitivity of pancreatic cancer cells to Gem by inhibiting autophagy and inducing apoptosis, providing a new strategy and potential treatment option for pancreatic cancer.

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.

scholarly journals Beclin1 inhibition promotes autophagy and decreases gemcitabine–induced apoptosis in Miapaca2 pancreatic cancer cells

2013 ◽  
Vol 13 (1) ◽  
pp. 26 ◽  
Author(s):  
Xiaoshu Li ◽  
Jun Yan ◽  
Lisheng Wang ◽  
Fengjun Xiao ◽  
Yuefeng Yang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Pancreatic Cancer Cells ◽  
Induced Apoptosis

scholarly journals Enhancement of cytotoxic effects of gemcitabine by Dclk1 inhibition through suppression of Chk1 phosphorylation in human pancreatic cancer cells

2017 ◽  
Vol 38 (5) ◽  
pp. 3238-3244 ◽  
Author(s):  
Daichi Kawamura ◽  
Yoshihiro Takemoto ◽  
Arata Nishimoto ◽  
Koji Ueno ◽  
Tohru Hosoyama ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Human Pancreatic Cancer ◽  
Cytotoxic Effects ◽  
Pancreatic Cancer Cells
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