scholarly journals The Role of F11R in Pancreatic Cancer Malignancy and Its Clinical Implication as a Therapeutic Target

2019 ◽  
Author(s):  
Haidi zhang ◽  
Chunyan Zhao ◽  
Xianhua Hu ◽  
Shuai He ◽  
Jinchuan Yu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Therapeutic Target ◽  
Immunoglobulin Superfamily ◽  
Experimental Conditions ◽  
Cycle Arrest ◽  
Pancreatic Cancer Cells ◽  
Promising Therapeutic Target ◽  
Cell Invasiveness

Abstract Abstract Background The F11 receptor belongs to the immunoglobulin superfamily and is expressed in epithelial and endothelial cells. F11R mediates the formation of tight junctions between the epithelium and endothelium, and participates in the invasion and metastasis of tumor cells. We have previously shown that the F11R gene is closely related to KRas (P= 0.76), a known therapeutic target for pancreatic cancer (PCa). In recent years, it has been found that F11R is expressed in different tumors and has biological effects.However, according to different tumor cases, different cell lines and experimental conditions, the regulatory results and mechanisms of F11R on tumor are different, even contradictory,and the expression, clinical significance and biological mechanism of F11R in tumor tissues have not been reported in detail. Results To investigate the role of F11R in carcinogenesis of PCa and the potential of F11R as a therapies target for PCa, we silenced F11R (-/-) in the PCa cell line PANC-1 (known to express high levels of KRas) using lentiviral approaches.We found that F11R silencing led to decreased cell proliferation, a loss of cell invasiveness, reduced colony forming ability, cell cycle arrest in G1 phase, cells apoptosis enhanced, and ros enhanced. In vitro data showed that inhibition of F11R decreased proliferation and invasiveness of cancer cells.The present results suggest that F11R may be a promising therapeutic target for PCa. Conclusions This study used bioinformatics combined with gene chip data to find the gene F11R, which is closely related to KRAS gene, and we used lentivirus to package shRNA plasmid to interfere with the gene F11R in pancreatic cancer panc-1 cells. A series of biobehavioral studies indicated the biobehavioral function and malignancy of panc-1 in pancreatic cancer cells with negative regulation of F11R gene.Based on this, we need to continue to clarify the expression of F11R gene in clinical case samples to determine whether F11R gene can be a new therapeutic target for pancreatic cancer.

scholarly journals Mesothelin blockage by Amatuximab suppresses cell invasiveness, enhances gemcitabine sensitivity and regulates cancer cell stemness in mesothelin-positive pancreatic cancer cells

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Fumihiko Matsuzawa ◽  
Hirofumi Kamachi ◽  
Tatsuzo Mizukami ◽  
Takahiro Einama ◽  
Futoshi Kawamata ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Morphological Changes ◽  
Pancreatic Cancer Cells ◽  
Cell Invasiveness ◽  
And Migration ◽  
Migration Capacity

Abstract Background Mesothelin is a 40-kDa glycoprotein that is highly overexpressed in various types of cancers, however molecular mechanism of mesothelin has not been well-known. Amatuximab is a chimeric monoclonal IgG1/k antibody targeting mesothelin. We recently demonstrated that the combine therapy of Amatuximab and gemcitabine was effective for peritonitis of pancreatic cancer in mouse model. Methods We discover the role and potential mechanism of mesothelin blockage by Amatuximab in human pancreatic cells both expressing high or low level of mesothelin in vitro experiment and peritonitis mouse model of pancreatic cancer. Results Mesothelin blockage by Amatuximab lead to suppression of invasiveness and migration capacity in AsPC-1 and Capan-2 (high mesothelin expression) and reduce levels of pMET expression. The combination of Amatuximab and gemcitabine suppressed proliferation of AsPC-1 and Capan-2 more strongly than gemcitabine alone. These phenomena were not observed in Panc-1 and MIA Paca-2 (Mesothelin low expression). We previously demonstrated that Amatuximab reduced the peritoneal mass in mouse AsPC-1 peritonitis model and induced sherbet-like cancer cell aggregates, which were vanished by gemcitabine. In this study, we showed that the cancer stem cell related molecule such as ALDH1, CD44, c-MET, as well as proliferation related molecules, were suppressed in sherbet-like aggregates, but once sherbet-like aggregates attached to peritoneum, they expressed these molecules strongly without the morphological changes. Conclusions Our work suggested that Amatuximab inhibits the adhesion of cancer cells to peritoneum and suppresses the stemness and viability of those, that lead to enhance the sensitivity for gemcitabine.

scholarly journals Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts

2019 ◽  
Vol 27 (8) ◽  
pp. 945-956 ◽  
Author(s):  
Yosuke Mitsui ◽  
Nahoko Tomonobu ◽  
Masami Watanabe ◽  
Rie Kinoshita ◽  
I Wayan Sumardika ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Motility ◽  
Cancer Cells ◽  
Cellular Migration ◽  
Mitogen Activated Protein Kinase ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells ◽  
Mechanistic Investigation

S100A11, a member of the S100 family of proteins, is actively secreted from pancreatic ductal adenocarcinoma (PDAC) cells. However, the role of the extracellular S100A11 in PDAC progression remains unclear. In the present study, we investigated the extracellular role of S100A11 in crosstalking between PDAC cells and surrounding fibroblasts in PDAC progression. An abundant S100A11 secreted from pancreatic cancer cells stimulated neighboring fibroblasts through receptor for advanced glycation end products (RAGE) upon S100A11 binding and was followed by not only an enhanced cancer cell motility in vitro but also an increased number of the PDAC-derived circulating tumor cells (CTCs) in vivo. Mechanistic investigation of RAGE downstream in fibroblasts revealed a novel contribution of a mitogen-activated protein kinase kinase kinase (MAPKKK), tumor progression locus 2 (TPL2), which is required for positive regulation of PDAC cell motility through induction of cyclooxygenase 2 (COX2) and its catalyzed production of prostaglandin E2 (PGE2), a strong chemoattractive fatty acid. The extracellularly released PGE2 from fibroblasts was required for the rise in cellular migration as well as infiltration of their adjacent PDAC cells in a coculture setting. Taken together, our data reveal a novel role of the secretory S100A11 in PDAC disseminative progression through activation of surrounding fibroblasts triggered by the S100A11‐RAGE‐TPL2‐COX2 pathway. The findings of this study will contribute to the establishment of a novel therapeutic antidote to PDACs that are difficult to treat by regulating cancer-associated fibroblasts (CAFs) through targeting the identified pathway.

Antifibrotic Agent Pirfenidone Suppresses Proliferation of Human Pancreatic Cancer Cells by Inducing G0/G1 Cell Cycle Arrest

Pharmacology ◽  
2019 ◽  
Vol 103 (5-6) ◽  
pp. 250-256 ◽  
Author(s):  
Eri Usugi ◽  
Kenichiro Ishii ◽  
Yoshifumi Hirokawa ◽  
Kazuki Kanayama ◽  
Chise Matsuda ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Human Pancreatic Cancer ◽  
Experimental Conditions ◽  
Cycle Arrest ◽  
Pancreatic Cancer Cells ◽  
G1 Cell Cycle Arrest

Background: Pirfenidone (PFD), which is an antifibrotic agent used for treatment of idiopathic pulmonary fibrosis, induces G0/G1 cell cycle arrest in fibroblasts. We hypothesized that PFD-induced G0/G1 cell cycle arrest might be achieved in other types of cells, including cancer cells. Here we investigated the effects of PFD on the proliferation of pancreatic cancer cells (PCCs) in vitro. Method: Human skin fibroblasts ASF-4-1 cells and human prostate stromal cells (PrSC) were used as fibroblasts. PANC-1, MIA PaCa-2, and BxPC-3 cells were used as human PCCs. Cell cycle and apoptosis were analyzed using flow cytometer. Results: First, we confirmed that PFD suppressed cell proliferation of ASF-4-1 cells and PrSC and induced G0/G1 cell cycle arrest. Under these experimental conditions, PFD also suppressed cell proliferation and induced G0/G1 cell cycle arrest in all PCCs. In PFD-treated PCCs, expression of p21 was increased but that of CDK2 was not clearly decreased. Of note, PFD did not induce significant apoptosis among PCCs. Conclusions: These results demonstrated that the antifibrotic agent PFD might have antiproliferative effects on PCCs by inducing G0/G1 cell cycle arrest. This suggests that PFD may target not only fibroblasts but also PCCs in the tumor microenvironment of pancreatic cancer.

scholarly journals HAT1 Promotes Gemcitabine Resistance by Regulating the PVT1/EZH2 Complex in Pancreatic Cancer

2020 ◽  
Author(s):  
Yan Sun ◽  
Jian Shen ◽  
Dianyun Ren ◽  
Yingke Zhou ◽  
Jingyuan Zhao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Statistical Significance ◽  
Gemcitabine Resistance ◽  
Development Of Resistance ◽  
Pancreatic Cancer Cells ◽  
Promising Therapeutic Target ◽  
The Relationship

Abstract Background: The poor prognosis of pancreatic cancer is primarily due to the development of resistance to therapies, including gemcitabine. PVT1 has been shown to interact with EZH2, promoting gemcitabine resistance in pancreatic cancer. Methods: In this study, we assessed the ability of PVT1/EZH2 targeting to reverse resistance to gemcitabine in pancreatic cancer cells. MTS assay, colony formation assay, and mouse xenotransplantation experiments were used to evaluate the anti-tumor effects of gemcitabine in HAT1 knockdown or overexpressing pancreatic cancer cells. The relationship between HAT1 and PVT1 in pancreatic cancer was determined by RNA sequencing, quantitative real-time PCR, and chromatin immunoprecipitation. Co-immunoprecipitation, pull-downs, western blotting, and immunohistochemistry were used to assess the relationship between HAT1 and EZH2 in pancreatic cancer. Chitosan (CS)-tripolyphosphate (TPP)-siHAT1 nanoparticles were developed to evaluate their effects on the anti-tumor potential of gemcitabine in pancreatic cancer. Student’s t-test, one-way analysis of variance (ANOVA), or two-way ANOVA was used to evaluate statistical significance. P-values <0.05 were considered statistically significant. All values were expressed as means ± SD. Results: Our results showed that the aberrant HAT1 expression promoted gemcitabine resistance in pancreatic cancer cells. We also found that HAT1 enhanced the binding of BRD4 to the PVT1 promoter, thereby promoting PVT1 transcription. Moreover, we found that HAT1 prevented EZH2 degradation by interfering with UBR4 binding to the N-terminal domain of EZH2, thus maintaining EZH2 protein stability. Finally, we showed that CS-TPP-siHAT1 nanoparticles augmented the anti-tumor effects of gemcitabine in pancreatic cancer cells in vitro and in vivo. Conclusions: Our findings suggest that by increasing the levels of the PVT1/EZH2 complex, HAT1 promotes gemcitabine resistance in pancreatic cancer. Therefore, HAT1 is a promising therapeutic target for pancreatic cancer.

scholarly journals Dihydroartemisinin induces apoptosis and downregulates glucose metabolism in JF-305 pancreatic cancer cells

RSC Advances ◽  
2018 ◽  
Vol 8 (37) ◽  
pp. 20692-20700
Author(s):  
Wenhe Zhu ◽  
Wei Zhang ◽  
Na Xu ◽  
Yawei Li ◽  
Junjie Xu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Glucose Metabolism ◽  
Cancer Treatment ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Therapeutic Target ◽  
Pancreatic Cancer Cells ◽  
Promising Therapeutic Target

Cancer cell promotion of glycolysis provides a promising therapeutic target for cancer treatment.

scholarly journals Telomerase and Pluripotency Factors Jointly Regulate Stemness in Pancreatic Cancer Stem Cells

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3145
Author(s):  
Karolin Walter ◽  
Eva Rodriguez-Aznar ◽  
Monica S. Ventura Ferreira ◽  
Pierre-Olivier Frappart ◽  
Tabea Dittrich ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Biology ◽  
Telomerase Activity ◽  
Pancreatic Cancer Cells ◽  
Sphere Formation ◽  
Telomerase Regulation ◽  
Pancreatic Cancer Stem Cells

To assess the role of telomerase activity and telomere length in pancreatic CSCs we used different CSC enrichment methods (CD133, ALDH, sphere formation) in primary patient-derived pancreatic cancer cells. We show that CSCs have higher telomerase activity and longer telomeres than bulk tumor cells. Inhibition of telomerase activity, using genetic knockdown or pharmacological inhibitor (BIBR1532), resulted in CSC marker depletion, abrogation of sphere formation in vitro and reduced tumorigenicity in vivo. Furthermore, we identify a positive feedback loop between stemness factors (NANOG, OCT3/4, SOX2, KLF4) and telomerase, which is essential for the self-renewal of CSCs. Disruption of the balance between telomerase activity and stemness factors eliminates CSCs via induction of DNA damage and apoptosis in primary patient-derived pancreatic cancer samples, opening future perspectives to avoid CSC-driven tumor relapse. In the present study, we demonstrate that telomerase regulation is critical for the “stemness” maintenance in pancreatic CSCs and examine the effects of telomerase inhibition as a potential treatment option of pancreatic cancer. This may significantly promote our understanding of PDAC tumor biology and may result in improved treatment for pancreatic cancer patients.

scholarly journals Stearoyl-CoA Desaturase 1 Potentiates Hypoxic plus Nutrient-Deprived Pancreatic Cancer Cell Ferroptosis Resistance

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Jie Gao ◽  
Zhengyang Zhang ◽  
Yanfang Liu ◽  
Zining Zhang ◽  
Ming Wang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Carcinoma ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Critical Role ◽  
Monounsaturated Fatty Acids ◽  
Pancreatic Cancer Cells ◽  
Stearoyl Coa Desaturase

Hypoxia and nutrient starvation (H/NS) microenvironment, a notable characteristic of pancreatic carcinoma, plays a critical role in cell death resistance and tumor recurrence. However, its role in ferroptosis remains to be classified. Here, we found that H/NS contributed to the pancreatic cancer cell ferroptosis resistance depending on the altered intracellular lipid compositions. Mechanistically, H/NS induced the upregulation of stearoyl-CoA desaturase 1 (SCD1), which promoted monounsaturated fatty acids (MUFAs) synthesis and protected against lipid peroxidation. Surprisingly, SCD1 showed a strong correlation with antiferroptosis gene expression. Moreover, short-hairpin RNA-based knockdown of SCD1 enhanced erastin-induced ferroptosis in vitro under H/NS. Finally, our results demonstrate the synergistic effect of erastin and A939572, a special SCD1 inhibitor, in dictating pancreatic carcinoma subcutaneous ferroptotic death. Taken together, our findings reveal a new role of the H/NS microenvironment against ferroptosis and suggest a potential therapeutic strategy for overcoming ferroptosis resistance in pancreatic cancer cells.

scholarly journals Gas Plasma-Conditioned Ringer’s Lactate Enhances the Cytotoxic Activity of Cisplatin and Gemcitabine in Pancreatic Cancer In Vitro and In Ovo

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 123 ◽  
Author(s):  
Kim-Rouven Liedtke ◽  
Eric Freund ◽  
Maraike Hermes ◽  
Stefan Oswald ◽  
Claus-Dieter Heidecke ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pancreatic Cancer ◽  
Cell Cycle Arrest ◽  
Human Pancreatic Cancer ◽  
In Ovo ◽  
Cycle Arrest ◽  
Pancreatic Cancer Cells ◽  
Gas Plasma ◽  
Ringer’S Lactate

Pancreatic cancer is one of the most aggressive tumor entities. Diffuse metastatic infiltration of vessels and the peritoneum restricts curative surgery. Standard chemotherapy protocols include the cytostatic drug gemcitabine with limited efficacy at considerable toxicity. In search of a more effective and less toxic treatment modality, we tested in human pancreatic cancer cells (MiaPaca and PaTuS) a novel combination therapy consisting of cytostatic drugs (gemcitabine or cisplatin) and gas plasma-conditioned Ringer’s lactate that acts via reactive oxygen species. A decrease in metabolic activity and viability, change in morphology, and cell cycle arrest was observed in vitro. The combination treatment was found to be additively toxic. The findings were validated utilizing an in ovo tumor model of solid pancreatic tumors growing on the chorion-allantois membrane of fertilized chicken eggs (TUM-CAM). The combination of the drugs (especially cisplatin) with the plasma-conditioned liquid significantly enhanced the anti-cancer effects, resulting in the induction of cell death, cell cycle arrest, and inhibition of cell growth with both of the cell lines tested. In conclusion, our novel combination approach may be a promising new avenue to increase the tolerability and efficacy of locally applied chemotherapeutic in diffuse metastatic peritoneal carcinomatosis of the pancreas.

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