scholarly journals Genetic Inactivation of Peroxiredoxin-I Impairs the Growth of Human Pancreatic Cancer Cells

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 570
Author(s):  
Hajar Dahou ◽  
Marie-Albane Minati ◽  
Patrick Jacquemin ◽  
Mohamad Assi
Keyword(s):  
Pancreatic Cancer ◽  
Oxidative Dna Damage ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Autophagic Flux ◽  
Pancreatic Cancer Cells ◽  
Ros Accumulation ◽  
Peroxiredoxin I

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with few therapeutic options. The identification of new promising targets is, therefore, an urgent need. Using available transcriptomic datasets, we first found that Peroxiredoxin-1 gene (PRDX1) expression was significantly increased in human pancreatic tumors, but not in the other gastrointestinal cancers; its high expression correlated with shortened patient survival. We confirmed by immunostaining on mouse pancreata the increased Peroxiredoxin-I protein (PRX-I) expression in pancreatic neoplastic lesions and PDAC. To question the role of PRX-I in pancreatic cancer, we genetically inactivated its expression in multiple human PDAC cell lines, using siRNA and CRISPR/Cas9. In both strategies, PRX-I ablation led to reduced survival of PDAC cells. This was mainly due to an increase in the production of reactive oxygen species (ROS), accumulation of oxidative DNA damage (i.e., 8-oxoguanine), and cell cycle blockade at G2/M. Finally, we found that PRX-I ablation disrupts the autophagic flux in PDAC cells, which is essential for their survival. This proof-of-concept study supports a pro-oncogenic role for PRX-I in PDAC.

Influence of IP-10/CXCL10 induction in human pancreatic cancer stroma on lymphocytes recruitment and correlation with survival.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 290-290 ◽  
Author(s):  
Thomas B Brunner ◽  
Serena Lunardi ◽  
Nigel B Jamieson ◽  
Su Yin Lim ◽  
Kristin L Griffiths ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cancer Patients ◽  
Mononuclear Cells ◽  
Pancreatic Stellate Cells ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Tumors ◽  
Pancreatic Cancer Cells

290 Background: Pancreatic ductal adenocarcinoma is characterized by an abundant desmoplastic reaction driven by pancreatic stellate cells (PSCs) that contributes to tumor progression. Here we sought to characterize the interactions between pancreatic cancer cells (PCCs) and PSCs that affect the inflammatory and immune response in pancreatic tumors. Methods: Conditioned media from mono- and cocultures of PSCs and PCCs were assayed for expression of cytokines, chemokines and growth factors. Gene expression analysis of human pancreatic ductal adenocarcinoma samples was used to verify expression of cytokines and their correlation with markers of immunoresponse and with clinical outcome. Finally, we tested chemotaxis of leukocytes isolated from peripheral blood mononuclear cells of pancreatic cancer patients. Results: IP-10/CXCL10 was the most highly induced chemokine in coculture of PSCs and PCCs. Its expression was induced in the PSCs by PCCs. IP-10 expression was consistently upregulated in human pancreatic cancer specimens, and positively correlated with high stroma content. Furthermore, expression of IP-10 and its receptor CXCR3 were significantly associated with the intratumoral presence of regulatory T cells (Tregs). In an independent cohort of 48 patients with resectable pancreatic ductal adenocarcinoma, the survival of patients with high IP-10 levels was 18.1 months less than those with low IP-10 levels (HR=2.14, 95% CI 1.05 -4.42). Importantly, IP-10 stimulated the ex vivo recruitment of CXCR3+ effector T cells as well as CXCR3+ Tregs derived from patients with pancreatic cancer. Conclusions: Our findings suggest that, in pancreatic cancer patients, CXCR3+ Tregs are recruited by IP-10 expressed by PSCs in the tumor stroma, leading to immunosuppressive and tumor-promoting effects.

Intra-Pancreatic Insulin Nourishes Cancer Cells: Do Insulin-Receptor Antagonists such as PGG and EGCG Play a Role?

2020 ◽  
Vol 48 (04) ◽  
pp. 1005-1019
Author(s):  
Lijuan Hu ◽  
Xijuan Chen ◽  
Shuai Qiu ◽  
Jing Yang ◽  
Hongyi Liu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Insulin Receptor ◽  
Cancer Cells ◽  
Human Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Pancreatic Cancer Cells ◽  
Pancreatic Insulin ◽  
Igf1r Expression ◽  
Expression And Activity

Harboring insulin-producing cells, the pancreas has more interstitial insulin than any other organ. In vitro, insulin activates both insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) to stimulate pancreatic cancer cells. Whether intra-pancreatic insulin nourishes pancreatic cancer cells in vivo remains uncertain. In the present studies, we transplanted human pancreatic cancer cells orthotopically in euglycemic athymic mice whose intra-pancreatic insulin was intact or was decreased following pretreatment with streptozotocin (STZ). In the next eight weeks, the tumor carriers were treated with one of the IR/IGF1R antagonists penta-O-galloyl-[Formula: see text]-D-glucose (PGG) and epigallocatechin gallate (EGCG) or treated with vehicle. When pancreatic tumors were examined, their fraction occupied with living cells was decreased following STZ pretreatment and/or IR/IGF1R antagonism. Using Western blot, we examined tumor grafts for IR/IGF1R expression and activity. We also determined proteins that were downstream to IR/IGF1R and responsible for signal transduction, glycolysis, angiogenesis, and apoptosis. We demonstrated that STZ-induced decrease in intra-pancreatic insulin reduced IR/IGF1R expression and activity, decreased the proteins that promoted cell survival, and increased the proteins that promoted apoptosis. These suggest that intra-pancreatic insulin supported local cancer cells. When tumor carriers were treated with PGG or EGCG, the results were similar to those seen following STZ pretreatment. Thus, the biggest changes in examined proteins were usually seen when STZ pretreatment and PGG/EGCG treatment concurred. This suggests that intra-pancreatic insulin normally combated pharmacologic effects of PGG and EGCG. In conclusion, intra-pancreatic insulin nourishes pancreatic cancer cells and helps the cells resist IR/IGF1R antagonism.

scholarly journals Differential Dependency of Human Pancreatic Cancer Cells on Targeting PTEN via PLK 1 Expression

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 277
Author(s):  
Jungwhoi Lee ◽  
Jungsul Lee ◽  
Woogwang Sim ◽  
Jae-Hoon Kim
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Intracellular Signaling ◽  
Biomarker Discovery ◽  
Human Pancreatic Cancer ◽  
Normal Tissues ◽  
Pancreatic Cancer Cells ◽  
Prognostic Implications ◽  
Plk1 Expression

Even though the tumour suppressive role of PTEN is well-known, its prognostic implications are ambiguous. The objective of this study was to further explore the function of PTEN expression in human pancreatic cancer. The expression of PTEN has been dominant in various human cancers including pancreatic cancer when compared with their matched normal tissues. The pancreatic cancer cells have been divided into PTEN blockade-susceptible and PTEN blockade-impassible groups dependent on targeting PTEN by altering intracellular signaling. The expression of PTEN has led to varying clinical outcomes of pancreatic cancer based on GEO Series (GSE) data analysis and Liptak’s z analysis. Differential dependency to PTEN blockade has been ascertained based on the expression of polo-like kinase1 PLK1 in pancreatic cancer cells. The prognostic value of PTEN also depends on PLK1 expression in pancreatic cancer. Collectively, the present study provides a rationale for targeting PTEN as a promising therapeutic strategy dependent on PLK1 expressions using a companion biomarker discovery platform.

Relationship between tissue factor expression by human pancreatic cancer cells and activation of coagulation and thrombosis in a mouse model.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14505-e14505
Author(s):  
Julia E. Geddings ◽  
Jian-guo Wang ◽  
Jessica C Cardenas ◽  
Pichika Chantrathammachart ◽  
Julie C Williams ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Tissue Factor ◽  
Saphenous Vein ◽  
Human Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Pancreatic Cancer Cells ◽  
Increased Risk ◽  
Patients At Risk

e14505 Background: The increased risk of thrombosis in patients with cancer has been well established. However, the triggers in these patients have yet to be fully defined. Under pathological conditions, the potent procoagulant protein Tissue Factor (TF) is found in the circulation and may trigger thrombosis. Methods: We evaluated the level of TF expression in 4 different human pancreatic cancer cell lines. We also measured TF microparticle (MP) release from these tumors in vivo by flow cytometry and TF activity assay. We then used these lines in a mouse model of pancreatic cancer to evaluate the sources of TF that activate coagulation and contribute to thrombosis using a saphenous vein model. Results: We found that mice bearing orthotopic pancreatic tumors which express higher levels of TF (HPAC and HPAF) show increased activation of coagulation (measured by thrombin-antithrombin complex) as compared to mice bearing TF negative tumors (MIA-PaCa-2 and PANC-1). This activation of coagulation could be reduced by treatment with a human TF antibody. Further, mice bearing tumors derived from TF high cell line HPAC demonstrated an activation of coagulation despite a lack of circulating TF-positive MPs. Mice bearing TF expressing pancreatic tumors also demonstrated increased thrombosis by a saphenous vein model. Treatment of tumor-free mice with TF MPs did not result in an activation of coagulation or increased thrombosis unless mice were given 40-100 fold higher levels of TF bearing MPs than are found in the circulation of tumor bearing mice. Conclusions: The data suggest that TF on the tumor itself is involved in the activation of coagulation whereas circulating TF-positive MPs is likely to contribute to thrombosis. Elevated levels of TF-positive MPs may be used as a biomarker to identify cancer patients at risk for thrombosis.

Possible role of autophagy inhibition in hypoxia-induced chemoresistance of pancreatic cancer cells.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 224-224 ◽  
Author(s):  
Yoon Ho Ko ◽  
Young-Seok Cho ◽  
Hye Sung Won ◽  
Eun Kyoung Jeon ◽  
Young Seon Hong
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Western Blotting ◽  
Pancreatic Cancer Cell Line ◽  
Cancer Cell Line ◽  
Hypoxic Condition ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells ◽  
Autophagy Inhibition

224 Background: Autophagy is a catabolic process and provides metabolic support for the cell by degradation of intracellular macromolecules. Various types of stress, including hypoxia, activate autophagy. Recent studies have suggested that hypoxia has been shown to associate with resistance to chemotherapy and radiation therapy and hence poor prognosis in pancreatic cancer. This study investigated the role of autophagy in the treatment of pancreatic cancer with gemcitabine under hypoxic condition. Methods: To evaluate the role of autophagy inhibition in hypoxia-induced chemoresistance, BxPC-3 human pancreatic cancer cell line was used under normoxic and hypoxic conditions.We evaluated the extent of LC3-II, as an autophagosome marker, induced by gemcitabine, by western blotting to measure the hypoxia- or chemotherapy- induced autophagy. We then examined the effects of gemcitabine on induction of apoptosis under normoxic and hypoxic conditions. Next, to determine the effect of 3-MA, a known inhibitor of autophagy, on overcoming hypoxia-induced chemoresistance, the MTS assay and flow cytometry were performed. Results: Compared with normoxia, gemcitabine-induced cell death under hypoxia was significantly decreased, as a result of the reduced apoptosis. Western blotting analysis demonstrated that LC3-II was increased under hypoxia, compared with normoxia.However, we found that 3-MA can enhance the growth inhibition and apoptotic effect of gemcitabine, even under hypoxia. These findings mean that autophagy mediates the chemoresistance under hypoxia. Conclusions: Activated autophagy plays a role in hypoxia-induced chemoresistance of pancreatic cancer cells. These findings may have important implications for future therapeutic strategies using gemcitabine against pancreatic cancer.

Use of high-resolution fluorescence laparoscopy with fluorophore-conjugated tumor-specific antibodies for the detection of pancreatic cancer metastasis invisible with standard laparoscopy.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 212-212
Author(s):  
Cristiina A. Metildi ◽  
Sharmeela Kaushal ◽  
Hop S. Tran Cao ◽  
Cynthia S. Snyder ◽  
Mark A. Talamini ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Light Source ◽  
Cancer Metastasis ◽  
False Negative ◽  
Human Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Primary Tumors ◽  
Led Light ◽  
Pancreatic Cancer Cells ◽  
Standard Laparoscopy

212 Background: Standard laparoscopy for pancreatic cancer often leads to false negative results, causing understaging of the disease. Improved sensitivity and resolution are necessary. Methods: Orthotopic and carcinomatosis mouse models of human pancreatic cancer were established with red fluorescent protein (RFP)-expressing or non-fluorescent BxPC-3 human pancreatic cancer cells. The mice with orthotopic unlabeled pancreatic cancer were administered Alexa 488- or 555-conjugated anti-CEA by tail-vein injection 2-4 weeks after tumor implantation. Diagnostic laparoscopy was performed with a Stryker L9000 LED light source or X8000 xenon light source 24 hours later. Pancreatic tumors were detected and localized under each light mode. After laparoscopy, intravital images were obtained with the OV-100 and Maestro CRI Small Animal Imaging Systems as positive controls. Tumors were collected for histologic analysis. Results: Fluorescence laparoscopy (FL) with the use of 495-nm excitation filter and an LED light source enabled more rapid and accurate identification and localization of primary tumors and metastases than bright light laparoscopy (BL). The use of fluorescent conjugates antibody-labeled tumors improved the accuracy of staging laparoscopy, increasing the sensitivity from 40% in BL to 96% in FL (p<0.001). FL was sufficiently sensitive to detect sub-millimeter tumor deposits that went undetected under BL. With adjustments to the LED light source, we could simultaneously detect tumor lesions of different fluorescent colors and surrounding structures with minimal autofluorescence. Conclusions: The use of FL and fluorophore-labeled anti-CEA antibodies permits rapid detection and accurate localization of primary and metastatic CEA-expressing human pancreatic cancer, including tumors that were undetectable with BL. The introduction of an LED light source allows simultaneous identification of fluorescent tumor of different wavelengths without compromising background illumination. Further development of this technology for clinical use can improve the staging and treatment of pancreatic cancer.

Effect of PPARδ Agonist on Stearoyl-CoA Desaturase 1 in Human Pancreatic Cancer Cells: Role of MEK/ERK1/2 Pathway

2015 ◽  
Vol 39 (2) ◽  
pp. 123-127 ◽  
Author(s):  
Shima Byagowi ◽  
Taghi Naserpour Farivar ◽  
Reza Najafipour ◽  
Mehdi Sahmani ◽  
Masoud Darabi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells ◽  
Stearoyl Coa Desaturase

scholarly journals Hypoxia-driven oncometabolite L-2HG maintains “stemness”-differentiation balance and facilitates immune suppression in pancreatic cancer

2020 ◽  
Author(s):  
Vineet K Gupta ◽  
Nikita S Sharma ◽  
Brittany Durden ◽  
Vanessa T Garrido ◽  
Kousik Kesh ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cell Activation ◽  
Immune Suppression ◽  
Human Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Isomeric Form ◽  
Spectrometric Analysis ◽  
Self Renewal ◽  
Pancreatic Cancer Cells ◽  
First Time

Abstract2-hydroxyglutarate (2-HG) has gained considerable importance in glioma and blood cancers that have mutations in the IDH1/2 gene. In the current study we show for the first time that pancreatic tumors produce 2HG in the absence of IDH1/2 mutation. Our study shows that hypoxic pancreatic tumors that have activated lactate dehydrogenase (LDH) activity, produce the L-isoform of 2HG.Metabolic mass spectrometric analysis along with chiral derivatization showed that pancreatic cancer cells as well as stromal cells secrete the L-isomeric form of 2-hydroxyglutarate (L-2HG) when exposed to hypoxic environment. Serum analysis of human pancreatic cancer patients also showed similar accumulation of L-2HG. Our results showed that this abnormally accumulated L-2HG regulates self-renewal by increasing expression of genes associated with stemness (Sox-2, CD133) and by decreasing expression of differentiation genes (Pdx-1, HB9, NKX6.1). Further analysis showed that secreted L-2HG mediates cross talk with immune T-cells and hampers their proliferation and migration thereby suppressing the anti-tumor immunity. In vivo targeting of LDH enzyme with inhibitor (GSK2837808A) showed decrease in L-2HG as well as subsequent tumor regression and sensitization to immune-checkpoint therapy.Present study shows for the first time that hypoxia mediated accumulation of L-2HG drives self-renewal in pancreatic cancer by shifting critical balance of gene expression towards stemness and promotes immune suppression by impairing T cell activation in this disease. Additionally, it indicates that targeting LDH can sensitize pancreatic tumors to anti-PD1 therapy by decreasing L-2HG and reverting their immune evasive function.

scholarly journals Growth Hormone Receptor Inhibition Sensitizes Human Pancreatic Cancer to Chemotherapy Treatments

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A1019-A1020
Author(s):  
Reetobrata Basu ◽  
John Joseph Kopchick ◽  
Silvana Duran Ortiz ◽  
Yanrong Qian ◽  
Prateek Kulkarni
Keyword(s):  
Pancreatic Cancer ◽  
Growth Hormone ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Hormone Receptor ◽  
Growth Hormone Receptor ◽  
Human Pancreatic Cancer ◽  
Drug Efflux ◽  
Pancreatic Cancer Cells

Abstract Human growth hormone (GH) and its cognate growth hormone receptor (GHR) have been established to have a distinct role in promoting the progression of several types of human cancers. We had earlier described a newfound role of the GH-GHR axis in driving chemoresistance in melanoma by upregulating drug efflux by ABC multidrug transporter expression and a phenotype switch by induction of epithelial-to-mesenchymal transition (EMT). Here we present an in-depth analysis of this role of GH-GHR in the highly therapy resistant human pancreatic cancer which has a 5-year survival rate of only 10% in 2020. Using human and mouse pancreatic cancer cells and RNA and protein expression analyses by RT-qPCR, ELISA, and western-blot, we identified that (i) GH upregulates specific ABC-transporter expressions in a drug-context specific manner, (ii) GH upregulates EMT transcription factors, (iii) GH activates specific oncogenic signaling pathways, and (iii) GH action increases cytochrome P450 members involved in hepatic drug metabolism. The GH antagonist, Pegvisomant, significantly inhibited these effects. Additionally, we confirmed the effects of these molecular changes by specific assays. For example, GH increases basement membrane invasion, viability of circulating tumor cells, and drug efflux; while inhibition of GHR by pegvisomant in pancreatic cancer cells reversed this aggressive tumor phenotype and sensitized the tumor cells to chemotherapy. Cell viability assays confirmed a decreased IC50 of gemcitabine, doxorubicin, and erlotinib in pancreatic cancer cells treated with pegvisomant and an increase in IC50 cells treated with GH. We further verified our results using in silico analyses of TCGA datasets for pancreatic cancer - which provided robust confirmation of our experimental findings. Presently we are validating our observation in nude mice with human pancreatic cancer cell xenografts. In conclusion, our in vitro results confirm that GHR antagonism can drastically sensitize human pancreatic cancer cells by blocking mechanisms of drug resistance, thus providing a valuable window for improved efficacy of available chemo- and targeted therapy.

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