scholarly journals The Significance of Targeting Poly (ADP-Ribose) Polymerase-1 in Pancreatic Cancer for Providing a New Therapeutic Paradigm

2021 ◽  
Vol 22 (7) ◽  
pp. 3509
Author(s):  
Keun-Yeong Jeong ◽  
Min Hee Park
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Adenosine Diphosphate ◽  
Pancreatic Cancer Cells ◽  
Distinct Subpopulation ◽  
Genome Wide ◽  
Cancer Cell Survival ◽  
Survival And Growth ◽  
Parp 1

Genome-wide studies focusing on elucidating the effects on cancer progression have enabled the consequent identification of a distinct subpopulation of pancreatic cancer cells with unstable genomic characteristics. Based on this background, deleterious changes by poly (adenosine diphosphate (ADP)-ribose) polymerase-1 (PARP)-1 have been concentrated in oncology. One of the critical functions of PARP-1 is the response to DNA damage, which plays a pivotal role in DNA repair in cancers. PARP-1 also has widespread functions that are essential for the survival and growth of cancer cells. It regulates oxidative stress in mitochondria through the regulation of superoxide and oxidation. PARP-1 is in charge of regulating mitosis, which is a crucial role in tumorigenesis and remodels histones and chromatin enzymes related to transcriptional regulation, causing alterations in epigenetic markers and chromatin structure. Given the significance of these processes, it can be understood that these processes in cancer cells are at the frontline of the pathogenetic changes required for cancer cell survival, and these contributions can result in malignant transformation. Therefore, this review addresses the current molecular biological features for understanding the multifactorial function of PARP-1 in pancreatic cancer related to the aforementioned roles, along with the summary of recent approaches with PARP-1 inhibition in clinical studies targeting pancreatic cancer. This understanding could help to embrace the importance of targeting PARP-1 in the treatment of pancreatic cancer, which may present the potential to find out a variety of research topics that can be both challenged clinically and non-clinically.

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 Functional Genome-wide Screening Identifies Targets and Pathways Sensitizing Pancreatic Cancer Cells to Dasatinib

2018 ◽  
Vol 9 (24) ◽  
pp. 4762-4773 ◽  
Author(s):  
Wenwen Chien ◽  
Makoto Sudo ◽  
Ling-Wen Ding ◽  
Qiao-Yang Sun ◽  
Peer Wuensche ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Pancreatic Cancer Cells ◽  
Genome Wide ◽  
Functional Genome

scholarly journals Genome-Wide Screening Reveals an EMT Molecular Network Mediated by Sonic Hedgehog-Gli1 Signaling in Pancreatic Cancer Cells

PLoS ONE ◽  
2012 ◽  
Vol 7 (8) ◽  
pp. e43119 ◽  
Author(s):  
Xuanfu Xu ◽  
Yingqun Zhou ◽  
Chuangao Xie ◽  
Shu-mei Wei ◽  
Huizhong Gan ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Sonic Hedgehog ◽  
Molecular Network ◽  
Pancreatic Cancer Cells ◽  
Genome Wide

scholarly journals Fusobacterium nucleatum infection induces pancreatic cancer cell proliferation and migration through regulation of host cytokine signaling

2021 ◽  
Author(s):  
Barath Udayasuryan ◽  
Tam T.D. Nguyen ◽  
Ariana Umana ◽  
LaDeidra Monet Roberts ◽  
Raffae A Ahmad ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Pancreatic Tumor ◽  
Pancreatic Cancer Cell ◽  
Fusobacterium Nucleatum ◽  
Cellular Migration ◽  
Gm Csf ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) harbors a complex tumor microbiome that has been implicated in cancer progression and resistance to chemotherapy. Recent clinical investigations uncovered a correlation between high loads of intratumor Fusobacterium nucleatum and decreased patient survival. Here we show that pancreatic cancer cell lines harboring intracellular F. nucleatum secrete elevated levels of cancer-associated cytokines including IL-8, CXCL1, GM-CSF, and MIP-3α. We report that GM-CSF directly increases the proliferation of pancreatic cancer cells, and contributes to increased cellular migration, notably in the absence of immune cell participation. This study is the first to investigate the direct impact of F. nucleatum infection on pancreatic cancer cells. Our results suggest that F. nucleatum within the pancreatic tumor microenvironment elicits infection-specific cytokine secretion that directly contributes adversely to cancer progression and warrants further research into therapeutic manipulation of the pancreatic tumor microbiome.

Effect of inhibition of poly-(ADP ribose) polymerase on gemcitabine and radiation-induced cytotoxicity of pancreatic cancer cells.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 203-203
Author(s):  
R. Tuli ◽  
A. Surmak ◽  
A. Blackford ◽  
A. Leubner ◽  
E. M. Jaffee ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Death ◽  
Dna Repair ◽  
Cancer Cells ◽  
Parp Inhibitor ◽  
Parp Inhibition ◽  
Pancreatic Cancer Cells ◽  
Synergistic Mechanism ◽  
Radiation Induced ◽  
Parp 1

203 Background: Poly-(ADP ribose) polymerases (PARPs) are DNA-binding proteins involved in DNA repair. PARP inhibition has resulted in excellent antitumor activity when used with other cytotoxic therapies. ABT-888 is a promising PARP inhibitor with excellent potency against the PARP-1/2 enzymes and good oral bioavailability. We attempt to determine whether PARP-1/2 inhibition alone, or in combination with gemcitabine, will enhance the effects of irradiation (RT) of pancreatic cancer cells. Methods: The pancreatic carcinoma cell lines, MiaPaCa-2 and Panc02, were treated with ABT-888, gemcitabine, RT, or combinations thereof. RT was delivered with a 137-Cs Gammacell in a single fraction. Cells were pre-treated once with ABT-888 and/or gemcitabine 30 minutes prior to RT. Viability was assessed through reduction of resazurin into fluorescent resorufin. Levels of apoptosis were determined by measuring caspase-3/7 activity using a luminescent assay. PARP activity was determined using a chemiluminescent PAR elisa. Results: The half maximal inhibitory concentration (IC50) of RT was 5 Gy; IC10 for ABT-888 and gemcitabine were 10 uM and 5 nM, respectively. Treatment with ABT-888 (10 uM), gemcitabine (5 nM), or combinations of the two with RT led to increasingly higher rates of cell death 8 days after treatment (p<0.001). RT dose enhancement factors were 1.5, 1.82 and 2.36 for 1, 10 and 100 uM ABT-888, respectively. Minimal cytotoxicity was noted when cells were treated with ABT-888 alone up to 100 uM. Caspase activity was not significantly increased when treated with ABT-888 (10 uM) alone (1.28 fold, p=0.077), but became significant when RT (2 Gy) was added (2.03 fold, p=0.006). This difference was further enhanced by the addition of gemcitabine (2.95 fold, p=0.004). Conclusions: ABT-888 is a potent radiosensitizer of pancreatic cancer cells with minimal cytotoxicity when used alone. Cell death is further potentiated by cotreatment with gemcitabine. Radiation-induced apoptosis was significantly enhanced by ABT-888 and gemcitabine, suggesting a synergistic mechanism of interference with DNA repair. These data are currently being validated in an orthotopic pancreatic cancer mouse model. No significant financial relationships to disclose.

Abstract LB-B05: Targeting IDH1 inhibits survival and growth of pancreatic cancer cells

2018 ◽  
Author(s):  
Ali Vaziri-Gohar ◽  
Katerina Dukleska ◽  
Jonathan R. Brody ◽  
Jordan M. Winter
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Pancreatic Cancer Cells ◽  
Survival And Growth

scholarly journals Ape1/Ref-1 Induces Glial Cell-Derived Neurotropic Factor (GDNF) Responsiveness by Upregulating GDNF Receptor α1 Expression

2009 ◽  
Vol 29 (8) ◽  
pp. 2264-2277 ◽  
Author(s):  
Mi-Hwa Kim ◽  
Hong-Beum Kim ◽  
Samudra Acharya ◽  
Hong-Moon Sohn ◽  
Jae Yeoul Jun ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Glial Cell ◽  
Cancer Progression ◽  
Neuronal Cell ◽  
Amyloid Peptide ◽  
Pancreatic Cancer Cells ◽  
Β Amyloid ◽  
Neurotropic Factor ◽  
Β Amyloid Peptide

ABSTRACT Apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1) dysregulation has been identified in several human tumors and in patients with a variety of neurodegenerative diseases. However, the function of Ape1/Ref-1 is unclear. We show here that Ape1/Ref-1 increases the expression of glial cell-derived neurotropic factor (GDNF) receptor α1 (GFRα1), a key receptor for GDNF. Expression of Ape1/Ref-1 led to an increase in the GDNF responsiveness in human fibroblast. Ape1/Ref-1 induced GFRα1 transcription through enhanced binding of NF-κB complexes to the GFRα1 promoter. GFRα1 levels correlate proportionally with Ape1/Ref-1 in cancer cells. The knockdown of endogenous Ape1/Ref-1 in pancreatic cancer cells markedly suppressed GFRα1 expression and invasion in response to GNDF, while overexpression of GFRα1 restored invasion. In neuronal cells, the Ape1/Ref-1-mediated increase in GDNF responsiveness not only stimulated neurite outgrowth but also protected the cells from β-amyloid peptide and oxidative stress. Our results show that Ape1/Ref-1 is a novel physiological regulator of GDNF responsiveness, and they also suggest that Ape1/Ref-1-induced GFRα1 expression may play important roles in pancreatic cancer progression and neuronal cell survival.

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