Prognostic Value and Molecular Mechanisms of Proteasome 26S Subunit, Non-ATPase Family Genes for Pancreatic Ductal Adenocarcinoma Patients after Pancreaticoduodenectomy

Background/Aims: Increasing evidence shows that reprogramming of energy metabolism is a hallmark of cancer. Considering the emergence of microRNAs as crucial modulators of cancer, this study aimed to better understand the molecular mechanisms of miR-124 in regulating glycolysis in human pancreatic cancer. Methods: RT-PCR was used to investigate the expression of monocarboxylate transporters (MCTs) in pancreatic ductal adenocarcinoma (PDAC) patient samples and the PANC-1 cell line. A public database and immunochemistry were used for comprehensive analysis of MCT1 expression. The targeting of MCT1 by miR-124 was predicted by software and validated for the MCT1 3’-UTR by dual-luciferase reporter analysis. Cell proliferation, apoptosis, migration, xenografting, and the intracellular pH and L-lactate levels were assessed. Hypoxia-inducible factor-α (HIF-1α) and lactate dehydrogenase A (LDH-A) expression levels were determined by RT-PCR and western blotting. Results: MCT1 expression was higher in PDAC tissue than in normal tissue. Inhibition of MCT1 affected lactate metabolism, resulting in a higher intracellular pH and less proliferation of PANC-1 cells. MCT1 was the target gene of miR-124. In in vitro experiments, miR-124 inhibited the glycolytic activity of PANC-1 cells by targeting MCT1, further decreasing the tumor phenotype by increasing the intracellular pH through LDH-A and HIF-1α. In in vivo experiments, overexpression of miR-124 and silencing of MCT1 significantly inhibited tumor growth. Conclusion: miR-124 inhibits the progression of PANC-1 by targeting MCT1 in the lactate metabolic pathway. Our findings provide novel evidence for further functional studies of miR-124, which might be useful for future therapeutic approaches to PDAC.

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Expression and Prognostic Value of Small Mothers Against Decapentaplegic 7, Matrix Metalloproteinase 2, and Matrix Metalloproteinase 9 in Resectable Pancreatic Ductal Adenocarcinoma

Pancreas ◽

10.1097/mpa.0000000000001892 ◽

2021 ◽

Vol 50 (8) ◽

pp. 1195-1201

Author(s):

Li Zhou ◽

Jun Lu ◽

Zhi-Yong Liang ◽

Wei-Xun Zhou ◽

Yi-Zhi Wang ◽

...

Keyword(s):

Matrix Metalloproteinase ◽

Pancreatic Ductal Adenocarcinoma ◽

Prognostic Value ◽

Matrix Metalloproteinase 9 ◽

Matrix Metalloproteinase 2 ◽

Ductal Adenocarcinoma ◽

Metalloproteinase 9

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Dissecting the Anticancer Mechanism of Trifluoperazine on Pancreatic Ductal Adenocarcinoma

Cancers ◽

10.3390/cancers11121869 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1869 ◽

Cited By ~ 4

Author(s):

Can Huang ◽

Wenjun Lan ◽

Nicolas Fraunhoffer ◽

Analía Meilerman ◽

Juan Iovanna ◽

...

Keyword(s):

Cell Death ◽

Pancreatic Ductal Adenocarcinoma ◽

Molecular Mechanisms ◽

Proteasome Inhibitors ◽

Ductal Adenocarcinoma ◽

Mitochondrial Stress ◽

Anticancer Mechanism ◽

Chemotherapeutic Treatment ◽

Approved Drugs ◽

Protein Response

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with almost no curative chemotherapeutic treatment. Besides the development of new compounds, repurposing of approved drugs to treat cancer, alone or in combination, has become an attractive strategy, showing many therapeutic and economic advantages. However, it is necessary to improve our knowledge about the mechanism of cell death elicited by approved drugs itself, but also to rationally develop more powerful multidrug treatments. In this work, we focus our attention on determining the mechanism promoting cell death following trifluoperazine (TFP) treatment, which is an antipsychotic drug with strong anticancer activity in PDAC. We demonstrate that TFP induces cell death by apoptosis and necroptosis, which can be partially inhibited by Z-VAD-FMK as well as necrostatin-1, respectively. This cell death promotion is triggered by a poor ATP content, observed in TFP-treated cells as a consequence of a dramatic decrease in OXPHOS metabolism due to mitochondrial stress. Remarkably, mitochondrial homeostasis was seriously affected, and a loss of mitochondrial membrane potential and ROS overproduction was observed. Moreover, this mitochondrial stress was coupled with an ER stress and the activation of the endoplasmic-reticulum-associated protein degradation (ERAD) and the unf olded protein response (UPR) pathways. We took advantage of this information and inhibited this process by using the proteasome inhibitors MG-132 or bortezomib compounds in combination with TFP and found a significant improvement of the anticancer effect of the TFP on primary PDAC-derived cells. In conclusion, this study not only uncovers the molecular mechanisms that are triggered upon TFP-treatment but also its possible combination with bortezomib for the future development of therapies for pancreatic cancer.

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Curation of the Pancreatic Ductal Adenocarcinoma Subset of the Cancer Genome Atlas Is Essential for Accurate Conclusions about Survival-Related Molecular Mechanisms

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-18-0290 ◽

2018 ◽

Vol 24 (16) ◽

pp. 3813-3819 ◽

Cited By ~ 17

Author(s):

Ivana Peran ◽

Subha Madhavan ◽

Stephen W. Byers ◽

Matthew D. McCoy

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Molecular Mechanisms ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Ductal Adenocarcinoma ◽

Cancer Genome Atlas ◽

Genome Atlas

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High JAK2 Protein Expression Predicts a Poor Prognosis in Patients with Resectable Pancreatic Ductal Adenocarcinoma

Disease Markers ◽

10.1155/2020/7656031 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Yang Song ◽

Mei-Yue Tang ◽

Wei Chen ◽

Zhe Wang ◽

Si-Liang Wang

Keyword(s):

Protein Expression ◽

Pancreatic Ductal Adenocarcinoma ◽

Poor Prognosis ◽

Prognostic Value ◽

Survival Curve ◽

Clinicopathological Features ◽

Ductal Adenocarcinoma ◽

Clinicopathological Analysis ◽

Primary Focus ◽

The Relationship

Background. Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies worldwide. The JAK/STAT signaling pathway is involved in pancreatic cancer tumorigenesis. However, the prognostic value of JAK2 expression in resectable PDAC is unclear. Method. In this study, we performed a clinicopathological analysis of 62 resectable PDAC cases with a primary focus on survival. JAK2 expression was examined by immunohistochemistry. The relationship between JAK2 expression and clinicopathological features and prognosis was analyzed. Results. Survival curve analyses revealed that high levels of JAK2 expression predict a poor prognosis in resectable PDAC patients. Multivariate analysis confirmed that JAK2 expression can predict the prognosis of PDAC. Conclusions. Assessment of JAK2 protein expression may be a promising method to predict prognosis in patients with resectable PDAC.

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