scholarly journals Dissecting the Anticancer Mechanism of Trifluoperazine on Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1869 ◽  
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.

scholarly journals miR-124 Suppresses Pancreatic Ductal Adenocarcinoma Growth by Regulating Monocarboxylate Transporter 1-Mediated Cancer Lactate Metabolism

2018 ◽  
Vol 50 (3) ◽  
pp. 924-935 ◽  
Author(s):  
De-Hai Wu ◽  
Hao Liang ◽  
Shou-Nan Lu ◽  
Hao Wang ◽  
Zhi-Lei Su ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Intracellular Ph ◽  
Molecular Mechanisms ◽  
Monocarboxylate Transporter ◽  
Human Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Luciferase Reporter ◽  
Lactate Metabolism ◽  
Rt Pcr ◽  
Monocarboxylate Transporter 1

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.

scholarly journals Bcl-2/Bcl-xL inhibitor ABT-737 sensitizes pancreatic ductal adenocarcinoma to paclitaxel-induced cell death

2017 ◽  
Vol 14 (1) ◽  
pp. 903-908 ◽  
Author(s):  
Shuya Kasai ◽  
Takuya Sasaki ◽  
Ayano Watanabe ◽  
Masao Nishiya ◽  
Shinji Yasuhira ◽  
...  
Keyword(s):  
Cell Death ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Ductal Adenocarcinoma

scholarly journals New Hope for Pancreatic Ductal Adenocarcinoma Treatment Targeting Endoplasmic Reticulum Stress Response: A Systematic Review

2018 ◽  
Vol 19 (9) ◽  
pp. 2468 ◽  
Author(s):  
Nuria Garcia-Carbonero ◽  
Weiyao Li ◽  
Marticela Cabeza-Morales ◽  
Javier Martinez-Useros ◽  
Jesus Garcia-Foncillas
Keyword(s):  
Systematic Review ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Early Stage ◽  
Stress Factors ◽  
Endoplasmic Reticulum Stress Response ◽  
Ductal Adenocarcinoma ◽  
Mutational Status ◽  
Chemotherapeutic Treatment

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of tumours, and its incidence is rising worldwide. Although survival can be improved by surgical resection when these tumours are detected at an early stage, this cancer is usually asymptomatic, and disease only becomes apparent after metastasis. Several risk factors are associated with this disease, the most relevant being chronic pancreatitis, diabetes, tobacco and alcohol intake, cadmium, arsenic and lead exposure, certain infectious diseases, and the mutational status of some genes associated to a familial component. PDAC incidence has increased in recent decades, and there are few alternatives for chemotherapeutic treatment. Endoplasmic reticulum (ER) stress factors such as GRP78/BiP (78 kDa glucose-regulated protein), ATF6α (activating transcription factor 6 isoform α), IRE1α (inositol-requiring enzyme 1 isoform α), and PERK (protein kinase RNA-like endoplasmic reticulum kinase) activate the transcription of several genes involved in both survival and apoptosis. Some of these factors aid in inducing a non-proliferative state in cancer called dormancy. Modulation of endoplasmic reticulum stress could induce dormancy of tumour cells, thus prolonging patient survival. In this systematic review, we have compiled relevant results concerning those endoplasmic reticulum stress factors involved in PDAC, and we have analysed the mechanism of dormancy associated to endoplasmic reticulum stress and its potential use as a chemotherapeutic target against PDAC.

scholarly journals NUCB1 Suppresses Growth and Shows Additive Effects With Gemcitabine in Pancreatic Ductal Adenocarcinoma via the Unfolded Protein Response

2021 ◽  
Vol 9 ◽  
Author(s):  
Yong-Qiang Hua ◽  
Ke Zhang ◽  
Jie Sheng ◽  
Zhou-Yu Ning ◽  
Ye Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Unfolded Protein Response ◽  
Calcium Binding ◽  
Ductal Adenocarcinoma ◽  
Additive Effects ◽  
Unfolded Protein ◽  
Pancreatic Cancer Cells ◽  
The Unfolded Protein Response ◽  
Protein Response

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor patient prognosis. A cellular stress response mechanism called the unfolded protein response (UPR) has been implicated in PDAC progression. More recently, nucleobindin 1 (NUCB1), a calcium-binding protein, has been shown to control the UPR but its precise role in PDAC has not been explored. Here, we found that downregulation of NUCB1 was associated with poor prognosis in patients with PDAC. Functionally, NUCB1 overexpression suppressed pancreatic cancer cell proliferation and showed additive effects with gemcitabine (GEM) in vitro and in vivo. Moreover, by controlling ATF6 activity, NUCB1 overexpression suppressed GEM-induced UPR and autophagy. Last but not least, we uncovered METTL3-mediated m6A modification on NUCB1 5′UTR via the reader YTHDF2 as a mechanism for NUCB1 downregulation in PDAC. Taken together, our study revealed crucial functions of NUCB1 in suppressing proliferation and enhancing the effects of gemcitabine in pancreatic cancer cells and identified METTL3-mediated m6A modification as a mechanism for NUCB1 downregulation in PDAC.

scholarly journals Diterpenoid Vinigrol activates ATF4/DDIT3-mediated PERK/eIF2α arm of unfolded protein response to drive breast cancer cell death

2021 ◽  
Author(s):  
Wencheng Wei ◽  
Yunfei Li ◽  
Chuanxi Wang ◽  
Sanxing Gao ◽  
Hao Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Unfolded Protein Response ◽  
Molecular Mechanisms ◽  
Death Process ◽  
Mcf7 Cells ◽  
Multiple Cancer ◽  
Unfolded Protein ◽  
Mechanistic Investigation ◽  
Anti Cancer ◽  
Protein Response

AbstractVinigrol is a natural diterpenoid with unprecedented chemical structure, driving great efforts into its total synthesis and the chemical analogs in the past decades. Despite its pharmacological efficacies reported on anti-hypertension and anti-clot, comprehensive functional investigations on Vinigrol and the underlying molecular mechanisms are entirely missing. In this study, we carried out a complete functional prediction of Vinigrol using a transcriptome-based strategy, Connectivity Map, and identified “anti-cancer” as the most prominent biofunction ahead of anti-hypertension and anti-depression/psychosis. A broad cytotoxicity was subsequently confirmed on multiple cancer types. Further mechanistic investigation on MCF7 cells revealed that its anti-cancer effect is mainly through activating PERK/eIF2α arm of unfolded protein response (UPR) and subsequent upregulation of p53/p21 to halt the cell cycle. The other two branches of UPR, IRE1α and ATF6, are functionally irrelevant to Vinigrol-induced cell death. CRISPR/Cas9-based gene activation, repression, and knockout systems identified essential contribution of ATF4/DDIT3 not ATF6 to the death process. This study unraveled a broad anti-cancer function of Vinigrol and its underlying targets and regulatory mechanisms, and also paved the way for further inspection on the structure-efficacy relationship of the whole compound family, making them a novel cluster of chemical hits for cancer therapy.

scholarly journals A Network-Based Approach for Identification of Subtype-Specific Master Regulators in Pancreatic Ductal Adenocarcinoma

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 155
Author(s):  
Yuchen Zhang ◽  
Lina Zhu ◽  
Xin Wang
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Network Inference ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Regulatory Mechanism ◽  
Expression Profiles ◽  
Strong Association ◽  
Predictive Biomarkers ◽  
Integrative Analysis ◽  
Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC), the predominant subtype of pancreatic cancer, has been reported with equal mortality and incidence for decades. The lethality of PDAC is largely due to its late presentation, when surgical resection is no longer an option. Similar to other major malignancies, it is now clear that PDAC is not a single disease, posing a great challenge to precise selection of patients for optimized adjuvant therapy. A representative study found that PDAC comprises four distinct molecular subtypes: squamous, pancreatic progenitor, immunogenic, and aberrantly differentiated endocrine exocrine (ADEX). However, little is known about the molecular mechanisms underlying specific PDAC subtypes, hampering the design of novel targeted agents. In this study we performed network inference that integrates miRNA expression and gene expression profiles to dissect the miRNA regulatory mechanism specific to the most aggressive squamous subtype of PDAC. Master regulatory analysis revealed that the particular subtype of PDAC is predominantly influenced by miR-29c and miR-192. Further integrative analysis found miR-29c target genes LOXL2, ADAM12 and SERPINH1, which all showed strong association with prognosis. Furthermore, we have preliminarily revealed that the PDAC cell lines with high expression of these miRNA target genes showed significantly lower sensitivities to multiple anti-tumor drugs. Together, our integrative analysis elucidated the squamous subtype-specific regulatory mechanism, and identified master regulatory miRNAs and their downstream genes, which are potential prognostic and predictive biomarkers.

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