scholarly journals Gemcitabine Induces Microvesicle Particle Release in a Platelet-Activating Factor-Receptor-Dependent Manner via Modulation of the MAPK Pathway in Pancreatic Cancer Cells

2018 ◽  
Vol 20 (1) ◽  
pp. 32 ◽  
Author(s):  
Anita Thyagarajan ◽  
Sayali Kadam ◽  
Langni Liu ◽  
Lisa Kelly ◽  
Christine Rapp ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Mapk Pathway ◽  
Platelet Activating Factor ◽  
Chemotherapeutic Agents ◽  
Acid Sphingomyelinase ◽  
Mitogen Activated Protein Kinase ◽  
Human Pancreatic Cancer ◽  
Dependent Manner ◽  
Pancreatic Cancer Cells

Studies, including ours, have shown that pro-oxidative stressors, such as chemotherapeutic agents, generate oxidized lipids with agonistic platelet-activating factor (PAF) activity. Importantly, recent reports have implicated that these PAF-agonists are transported extracellularly via microvesicle particles (MVPs). While the role of PAF-receptor (PAF-R) has been implicated in mediating chemotherapy effects, its significance in chemotherapy-mediated MVP release in pancreatic cancer has not been studied. The current studies determined the functional significance of PAF-R in gemcitabine chemotherapy-mediated MVP release in human pancreatic cancer cells. Using PAF-R-expressing (PANC-1) and PAF-R-deficient (Hs766T) cells, we demonstrate that gemcitabine induces MVP release in a PAF-R-dependent manner. Blocking of PAF-R via PAF-R antagonist or inhibition of MVP generation via inhibitor of acid sphingomyelinase (aSMase) enzyme, significantly attenuated gemcitabine-mediated MVP release from PANC-1 cells, however, exerted no effects in Hs766T cells. Notably, MVPs from gemcitabine-treated PANC-1 cells, contained a measurable amount of PAF-agonists. Mechanistically, pretreatment with ERK1/2 or p38 inhibitors significantly abrogated gemcitabine-mediated MVP release, indicating the involvement of mitogen-activated protein kinase (MAPK) pathway in PAF-R-dependent gemcitabine-mediated MVP release. These findings demonstrate the significance of PAF-R in gemcitabine-mediated MVP release, as well as the rationale of evaluating PAF-R targeting agents with gemcitabine against pancreatic cancer.

Opposing Oncogenic Functions of p38 Mitogen-activated Protein Kinase Alpha and Beta in Human Pancreatic Cancer Cells

2020 ◽  
Vol 40 (10) ◽  
pp. 5545-5556
Author(s):  
XIAODONG TIAN ◽  
BENNO TRAUB ◽  
XUEHAI XIE ◽  
SHAOXIA ZHOU ◽  
DORIS HENNE-BRUNS ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Protein Kinase ◽  
Cancer Cells ◽  
Mitogen Activated Protein Kinase ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells ◽  
Mitogen Activated Protein

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.

scholarly journals The Ibr-7 Derivative of Ibrutinib Exhibits Radiosensitivity in Pancreatic Cancer Cells via Targeting EGFR

2020 ◽  
Author(s):  
Biqin Tan ◽  
Bo Zhang ◽  
Youyou Yan ◽  
Qingyu Li ◽  
Fei Wang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cell Apoptosis ◽  
Human Pancreatic Cancer ◽  
Dependent Manner ◽  
Immunofluorescence Analysis ◽  
Proliferative Effect ◽  
Pancreatic Cancer Cells ◽  
Radiation Group ◽  
M Phase

Abstract Background: Radiotherapy is one of the main therapeutic methods for pancreatic cancer, but radiation resistance limits the clinical application. As a result, novel therapeutic agents to improve the radiosensitivity is urgent. This study aimed to investigate the effect of Ibr-7 (the derivative of ibrutinib) on radiosensitivity of human pancreatic cancer cells.Methods: The effect of Ibr-7 on pancreatic cancer cell’s proliferation were detected by CCK-8 assay. Radiosensitivity was assessed by clonogenic formation assay. Cell cycle, cell apoptosis were analyzed by flow cytometry. DNA damage was detected by immunofluorescence analysis. The expression of p-EGFR, EGFR were determined by western blot.Results: Ibr-7 showed anti-proliferative effect in PANC-1 and Capan2 cells in a dose- and time-dependent manner. Ibr-7 (2 µmol/L) enhanced the effect of radiation in PANC-1 and Capan2 cells. Further findings showed that this combination enhanced G2/M phase arrest and increased cell apoptosis. Additional molecular mechanism studies revealed that the expression of p-EGFR was decreased by Ibr-7 alone or combined with radiation. Overexpression of EGFR reversed the cell apoptosis induced by Ibr-7 combined with radiation. Moreover, the expression of γ-H2AX was significantly decreased in Ibr-7 combined with radiation group.Conclusions: Our study indicated that the potential application of Ibr-7 as a highly effective radiosensitizer for the treatment of pancreatic cancer cells.

scholarly journals Dual Effects of Silibinin on Human Pancreatic Cancer Cells

2020 ◽  
Author(s):  
Su-Mi Lee ◽  
Gil-Woo Lee ◽  
Seon-Young Park ◽  
Hosouk Joung ◽  
Chang-Hwan Park ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Human Pancreatic Cancer ◽  
Dependent Manner ◽  
Protein Levels ◽  
Ductal Cells ◽  
Pancreatic Cancer Cells ◽  
Anticancer Effects ◽  
Pancreatic Cells ◽  
Dose Dependent

Abstract Background Silibinin is a flavonoid with antihepatotoxic properties, and exhibits pleiotropic anticancer effects. However, the molecular mechanisms responsible for its anticancer actions in pancreatic cancer cells, and the effects on such cells and normal pancreatic cells, remain unclear. The objective of this study was to determine the effect of silibinin on human pancreatic cancer cells and normal ductal cells.Methods Human pancreatic cancer cells (MIA PaCa-2 and PANC-1) and normal ductal cells (hTERT-HPNE) were cultured with 0–400 μM silibinin for 48 h. Thereafter, the proliferation, invasion, apoptosis, and signaling pathways of the pancreatic cells were evaluated.Results Silibinin significantly inhibited the proliferation, invasion, and spheroid formation of human pancreatic cancer cells in vitro in a dose-dependent manner (p < 0.05). It also induced apoptosis in a dose-dependent manner. Western blot analysis showed that silibinin downregulated extracellular signaling-regulated kinase (ERK) and serine/threonine protein kinase (AKT) in human pancreatic cancer cells. It also upregulated microtubule associated protein 1 light chain 3 β (LC3B) and cleaved caspase-3 via c-Jun N-terminal kinases (JNK) signaling. On the other hand, silibinin increased the mRNA and protein levels of c-Jun, Twist-related protein 1, and Snail. It also decreased exogenous p53 levels, but increased endogenous c-Jun protein levels in human pancreatic cancer cells. However, silibinin did not affect cell viability and endogenous c-Jun levels in pancreatic normal ductal cells. It increased exogenous p53 levels, but decreased stemness-related gene expression in pancreatic normal ductal cells. Silibinin increased Ki-67 levels in pancreatic cancer cells, but decreased them in pancreatic normal ductal cells.Conclusion Silibinin not only exerted anticancer effects by inhibiting AKT–ERK and JNK signaling, but also upregulated cancer stemness–related genes in human pancreatic cancer cells. These results suggest that silibinin should be used as a therapeutic agent for human pancreatic cancer with caution.

scholarly journals Antiproliferative and Antimigration Activities of Beauvericin Isolated from Isaria sp. on Pancreatic Cancer Cells

Molecules ◽  
2020 ◽  
Vol 25 (19) ◽  
pp. 4586
Author(s):  
Hiroaki Yahagi ◽  
Tadahiro Yahagi ◽  
Megumi Furukawa ◽  
Keiichi Matsuzaki
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Anticancer Agent ◽  
Culture Broth ◽  
Human Pancreatic Cancer ◽  
Dependent Manner ◽  
Migration Activity ◽  
Etoac Extract ◽  
Pancreatic Cancer Cells ◽  
Dose Dependent

This study describes the antiproliferative and antimigration effects of beauvericin from a culture broth of Isaria sp. in human pancreatic cancer cells (PANC-1). Activity-guided fractionation of the EtOAc extract of cultured broth of Isaria sp. RD055140 afforded beauvericin (1), a new isariotin derivative, 7-O-methylisariotin C (2), together with the known isariotin analogs, TK-57-164A (3) and B (4). As a result of the measurement of the cell viability, 1 inhibited cell growth (IC50 = 4.8 µM) of PANC-1 cells. Furthermore, 1 was found to inhibit the migration activity of PANC-1 cells by upregulating the expression of the E-cadherin gene and reducing N-cadherin and Snail genes in a dose-dependent manner (0.1–1 µM). These activities of 1 had lower concentrations than the cytotoxic activity. These findings suggest that 1 can be used as an anticancer agent against human pancreatic carcinoma.

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