scholarly journals Procathepsin E is highly abundant but minimally active in pancreatic ductal adenocarcinoma tumors

2016 ◽  
Vol 397 (9) ◽  
pp. 871-881 ◽  
Author(s):  
Anthony J. O’Donoghue ◽  
Sam L. Ivry ◽  
Chaity Chaudhury ◽  
Daniel R. Hostetter ◽  
Douglas Hanahan ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Immunoblot Analysis ◽  
Pancreatic Tissue ◽  
Tumor Burden ◽  
Ductal Adenocarcinoma ◽  
Aspartyl Protease ◽  
Altered Expression ◽  
Cathepsin E ◽  
Stage Disease ◽  
End Stage

Abstract The cathepsin family of lysosomal proteases is increasingly being recognized for their altered expression in cancer and role in facilitating tumor progression. The aspartyl protease cathepsin E is overexpressed in several cancers and has been investigated as a biomarker for pancreatic ductal adenocarcinoma (PDAC). Here we show that cathepsin E expression in mouse PDAC tumors is increased by more than 400-fold when compared to healthy pancreatic tissue. Cathepsin E accumulates over the course of disease progression and accounts for more than 3% of the tumor protein in mice with end-stage disease. Through immunoblot analysis we determined that only procathepsin E exists in mouse PDAC tumors and cell lines derived from these tumors. By decreasing the pH, this procathepsion E is converted to the mature form, resulting in an increase in proteolytic activity. Although active site inhibitors can bind procathepsin E, treatment of PDAC mice with the aspartyl protease inhibitor ritonavir did not decrease tumor burden. Lastly, we used multiplex substrate profiling by mass spectrometry to identify two synthetic peptides that are hydrolyzed by procathepsin E near neutral pH. This work represents a comprehensive analysis of procathepsin E in PDAC and could facilitate the development of improved biomarkers for disease detection.

Clinical significance of cathepsin E in pancreatic juice in the diagnosis of pancreatic ductal adenocarcinoma

2000 ◽  
Vol 15 (11) ◽  
pp. 1333-1338 ◽  
Author(s):  
Koji Uno ◽  
Takeshi Azuma ◽  
Masatsugu Nakajima ◽  
Kenjiro Yasuda ◽  
Takanobu Hayakumo ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Clinical Significance ◽  
Pancreatic Juice ◽  
Ductal Adenocarcinoma ◽  
Cathepsin E

scholarly journals Betulinic Acid Affects the Energy-Related Proteomic Profiling in Pancreatic Ductal Adenocarcinoma Cells

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2482
Author(s):  
Ching-Feng Chiu ◽  
Hsin-Yi Chang ◽  
Chun-Yine Huang ◽  
Chen-Zou Mau ◽  
Tzu-Ting Kuo ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Betulinic Acid ◽  
Expression Patterns ◽  
Apolipoprotein A1 ◽  
Ductal Adenocarcinoma ◽  
Therapeutic Window ◽  
Pdac Cell ◽  
Cell Growth And Migration ◽  
Altered Expression ◽  
Clinical Prognosis

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a 5-year survival rate of <8%. Therefore, finding new treatment strategies against PDAC cells is an imperative issue. Betulinic acid (BA), a plant-derived natural compound, has shown great potential to combat cancer owing to its versatile physiological functions. In this study, we observed the impacts of BA on the cell viability and migratory ability of PDAC cell lines, and screened differentially expressed proteins (DEPs) by an LC-MS/MS-based proteomics analysis. Our results showed that BA significantly inhibited the viability and migratory ability of PDAC cells under a relatively low dosage without affecting normal pancreatic cells. Moreover, a functional analysis revealed that BA-induced downregulation of protein clusters that participate in mitochondrial complex 1 activity and oxidative phosphorylation, which was related to decreased expressions of RNA polymerase mitochondrial (POLRMT) and translational activator of cytochrome c oxidase (TACO1), suggesting that the influence on mitochondrial function explains the effect of BA on PDAC cell growth and migration. In addition, BA also dramatically increased Apolipoprotein A1 (APOA1) expression and decreased NLR family CARD domain-containing protein 4 (NLRC4) expression, which may be involved in the dampening of PDAC migration. Notably, altered expression patterns of APOA1 and NLRC4 indicated a favorable clinical prognosis of PDAC. Based on these findings, we identified potential proteins and pathways regulated by BA from a proteomics perspective, which provides a therapeutic window for PDAC.

scholarly journals Targeting PI3K Pathway in Pancreatic Ductal Adenocarcinoma: Rationale and Progress

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4434
Author(s):  
Siddharth Mehra ◽  
Nilesh Deshpande ◽  
Nagaraj Nagathihalli
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Pi3k Pathway ◽  
Tumor Burden ◽  
Ductal Adenocarcinoma ◽  
Cancer Type ◽  
Therapeutic Implications ◽  
Downstream Signaling ◽  
Genetic Mouse Model ◽  
Dismal Prognosis ◽  
Effector Pathways

Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest solid tumors that remain treatment-refractory and show a dismal prognosis. More than 90% of PDAC tumors harbor mutations in the K-Ras that exert a strong pro-tumorigenic effect by activating several downstream effector pathways, including phosphatidylinositol-3-kinase (PI3K)-Akt. The role of frequently activated PI3K/Akt pathway in promoting PDAC aggressiveness is well established. Therapeutic approaches targeting PI3K and downstream signaling components in different cellular compartments, including tumor, stromal and immune cells, have directly impacted the tumor burden in this cancer type. Our previous work has demonstrated that targeting the PI3K/Akt/mTOR pathway reduced tumor growth and improved survival in the genetic mouse model of PDAC. Here, we discuss the significance of targeting PI3K signaling and the biological impact of PI3K inhibition in modulating the tumor–stromal immune crosstalk within the microenvironment of pancreatic cancer. Furthermore, this review updates on the current challenges involving the therapeutic implications of targeting this pathway in PDAC.

Abstract PO-061: The role of Cathepsin E expression in pancreatic ductal adenocarcinoma tumorigenesis

2020 ◽  
Author(s):  
Ericka Velez-Bonet ◽  
Sabrina Kaul ◽  
Corbin Pontious ◽  
Marcus Hong ◽  
Kelly Dubai ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma ◽  
Cathepsin E

scholarly journals Integrated Bioinformatics Analysis of Gene Expression Profiles for Potential Biomarker Identification Towards Early Therapeutic Intervention in Pancreatitis and Pancreatic Ductal Adenocarcinoma

2021 ◽  
Author(s):  
Manoj M Wagle ◽  
Ananya Rao Kedige ◽  
Shama P Kabekkodu ◽  
Sandeep Mallya
Keyword(s):  
Gene Expression ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Bioinformatics Analysis ◽  
Ductal Adenocarcinoma ◽  
Rapid Progression ◽  
Hub Genes ◽  
Altered Expression ◽  
Biochemical Pathways ◽  
Potential Biomarker ◽  
Key Genes

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a malignancy associated with rapid progression and an abysmal prognosis. It has been reported that chronic pancreatitis can increase the risk of developing PDAC by 16-fold. Our study aims to identify the key genes and biochemical pathways mediating pancreatitis and PDAC. The gene expression datasets were retrieved from the EMBL-EBI ArrayExpress and NCBI GEO database. A total of 172 samples of normal pancreatic tissue, 68 samples of pancreatitis, and 306 samples of PDAC were used in this study. The differentially expressed genes (DEGs) identified were used to perform downstream analysis for ontology, interaction, and associated pathways. Furthermore, hub gene expression was validated using the GEPIA2 tool and survival analysis using the Kaplan-Meier (KM) plotter. The potential druggability of the hub genes identified was determined using the Drug-Gene Interaction Database (DGIdb). Our study identified a total of 45 genes found to have altered expression levels in both PDAC and pancreatitis. Over-representation analysis revealed that protein digestion and absorption pathway, ECM-receptor interaction pathway, PI3k-Akt signaling pathway, and proteoglycans in cancer pathways as significantly enriched. Module analysis revealed 15 hub genes with 92 edges, of which 14 were found to be in the druggable genome category. Through bioinformatics analysis, we identified key genes and biochemical pathways disrupted in pancreatitis and PDAC. The results can provide new insights into targeted therapy and intervening therapeutically at an earlier stage can be used as an effective strategy to decrease the incidence and severity of PDAC.

Utility of CT Radiomics Features in Differentiation of Pancreatic Ductal Adenocarcinoma From Normal Pancreatic Tissue

2019 ◽  
Vol 213 (2) ◽  
pp. 349-357 ◽  
Author(s):  
Linda C. Chu ◽  
Seyoun Park ◽  
Satomi Kawamoto ◽  
Daniel F. Fouladi ◽  
Shahab Shayesteh ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Pancreatic Tissue ◽  
Ductal Adenocarcinoma ◽  
Normal Pancreatic Tissue

Clinical significance of cathepsin E in pancreatic juice in the diagnosis of pancreatic ductal adenocarcinoma

2000 ◽  
Vol 15 (11) ◽  
pp. 1333-1338 ◽  
Author(s):  
Koji Uno ◽  
Takeshi Azuma ◽  
Masatsugu Nakajima ◽  
Kenjiro Yasuda ◽  
Takanobu Hayakumo ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Clinical Significance ◽  
Pancreatic Juice ◽  
Ductal Adenocarcinoma ◽  
Cathepsin E

scholarly journals The clinicopathological significance of forkhead box P1 and forkhead box O3a in pancreatic ductal adenocarcinomas

Tumor Biology ◽  
2017 ◽  
Vol 39 (5) ◽  
pp. 101042831769912 ◽  
Author(s):  
Xin Luo ◽  
Zhulin Yang ◽  
Xiao Liu ◽  
Ziru Liu ◽  
Xiongying Miao ◽  
...  
Keyword(s):  
Protein Expression ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Poor Prognosis ◽  
Ductal Adenocarcinoma ◽  
Tumor Node Metastasis ◽  
Tumor Mass ◽  
Node Metastasis ◽  
Forkhead Box ◽  
Stage Disease ◽  
Forkhead Box O3a

Pancreatic ductal adenocarcinoma is a highly malignant tumor with poor prognosis, and the biomarkers for the early diagnosis, targeting therapy, and prognosis are still not clinically available. This study investigated the expression of forkhead box P1 and forkhead box O3a proteins in human pancreatic ductal adenocarcinoma tumor tissues and pancreatic tissues with and without benign lesions using immunohistochemical staining. Results showed that the positive rates of forkhead box P1 and forkhead box O3a protein expression were significantly lower in pancreatic ductal adenocarcinoma tumors compared to peritumoral tissues, benign pancreatic tissues, and normal pancreatic tissues (p < 0.01). Pancreatic tissues with negative forkhead box P1 and forkhead box O3a protein expression exhibited dysplasia or intraepithelial neoplasia. The positive rates of forkhead box P1 and forkhead box O3a expression were significantly lower in cases with tumor mass >5 cm, lymph node metastasis, invasion to surrounding tissues and organs, and tumor–node–metastasis III + IV stage disease compared to cases with tumor mass ⩽5 cm (p < 0.05), no lymph node metastasis (p < 0.001 and p = 0.001, respectively), no invasion (p = 0.003 and p = 0.004, respectively), and tumor–node–metastasis I or II stage disease (p < 0.05). Kaplan–Meier survival analysis showed that pancreatic ductal adenocarcinoma patients with negative forkhead box P1 and forkhead box O3a expression survived significantly shorter than patients with positive forkhead box P1 and forkhead box O3a expression (p = 0.000). Cox multivariate analysis revealed that negative forkhead box P1 and forkhead box O3a expression was an independent poor prognosis factor in pancreatic ductal adenocarcinoma patients. The area under the curve of a receiver operating characteristic curve was 0.642 for forkhead box P1 (95% confidence interval: 0.553–0.730) and 0.655 for forkhead box O3a (95% confidence interval: 0.6568–0.742). Loss of forkhead box P1 and forkhead box O3a protein expression is associated with carcinogenesis, progression, and poor prognosis in patients with pancreatic ductal adenocarcinomas.

scholarly journals Dysregulation of miRNAs Targeting the IGF-1R Pathway in Pancreatic Ductal Adenocarcinoma

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1856
Author(s):  
Maria Dobre ◽  
Vlad Herlea ◽  
Cătălina Vlăduţ ◽  
Mihai Ciocîrlan ◽  
Vasile Daniel Balaban ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Signaling Pathway ◽  
Treatment Options ◽  
Therapy Resistance ◽  
Pancreatic Disease ◽  
Pancreatic Tissue ◽  
Ductal Adenocarcinoma ◽  
Normal Tissues ◽  
Pdac Tissue

Background: Pancreatic ductal adenocarcinoma (PDAC), the most prevalent neoplastic lethal pancreatic disease, has a poor prognosis and an increasing incidence. The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is considered to be a contributing factor to the progression, metastasis, and therapy resistance of PDAC. Currently available treatment options for PDAC are limited, but microRNAs (miRNAs) may represent a new therapeutic strategy for targeting genes involved in the IGF-1R signaling pathway. Method: We investigated the expression levels of 21 miRNAs involved in the IGF-1R signaling pathway in pancreatic tissue from 38 patients with PDAC and 11 controls (five patients with chronic pancreatitis and six patients with normal pancreatic tissue). Results: We found 19 differentially expressed miRNAs between the PDAC cases and the controls. In particular, miR-100-5p, miR-145-5p, miR-29c-3p, miR-9-5p, and miR-195-5p were exclusively downregulated in PDAC tissue but not in chronic pancreatitis or normal pancreatic tissues; both control types presented similar levels. We also identified miR-29a-3p, miR-29b-3p, and miR-7-5p as downregulated miRNAs in PDAC tissues as compared with normal tissues but not with pancreatitis tissues. Conclusions: We identified a panel of miRNAs that could represent putative therapeutic targets for the development of new miRNA-based therapies for PDAC.

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