Targeted Delivery of C/EBPα -saRNA by Pancreatic Ductal Adenocarcinoma-specific RNA Aptamers Inhibits Tumor Growth In Vivo

It has been shown that aberrant activation of the Hedgehog (Hh) and nuclear factor-kappa B (NF-κB) signaling pathways plays an important role in the pancreatic carcinogenesis, and KRAS mutation is a hallmark of pancreatic ductal adenocarcinoma (PDAC). Until now, the role of KRAS mutation in the context of crosstalk between Hh and NF-κB signaling pathways in PDAC has not been investigated. This study was to determine whether the crosstalk between the Hh and NF-κB pathways is dependent on KRAS mutation in PDAC. The correlation between Gli1, Shh, NF-κB p65 expression and KRAS mutation in PDAC tissues was firstly examined by immunohistochemistry. Next, Western blotting, qPCR, and immunofluorescence were conducted to examine the biological effects of interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α) as NF-κB signaling agonists, Shh as an Hh ligand alone or in combination with KRAS small interfering RNA (si-KRAS) in KRAS-mutant PDAC cells (MT-KRAS; SW1990 and Panc-1), wild-type KRAS PDAC cells (WT-KRAS; BxPC-3) and mutant KRAS knock-in BxPC-3 cells in vitro as well as tumor growth in vivo. KRAS mutation-dependent crosstalk between Hh and NF-κB in PDAC cells was further assessed by Ras activity and luciferase reporter assays. The aberrant Hh and NF-κB pathway activation was found in PDAC tissues with KRAS mutation. The same findings were confirmed in MT-KRAS PDAC cells and MT-KRAS knock-in BxPC-3 cells, whereas this activation was not observed in WT-KRAS PDAC cells. However, the activation was significantly down-regulated by KRAS silencing in MT-KRAS PDAC cells. Furthermore, MT-KRAS cancer cell proliferation and survival in vitro and tumor growth after inoculation with MT-KRAS cells in vivo were promoted by NF-κB and Hh signaling activation. The pivotal factor for co-activation of NF-κB and Hh signaling is MT-KRAS protein upregulation, showing that positive crosstalk between Hh and NF-κB pathways is dependent upon KRAS mutation in PDAC.

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Octyl Gallate Induces Pancreatic Ductal Adenocarcinoma Cell Apoptosis and Suppresses Endothelial-Mesenchymal Transition-Promoted M2-Macrophages, HSP90α Secretion, and Tumor Growth

Cells ◽

10.3390/cells9010091 ◽

2019 ◽

Vol 9 (1) ◽

pp. 91

Author(s):

Kee Voon Chua ◽

Chi-Shuan Fan ◽

Chia-Chi Chen ◽

Li-Li Chen ◽

Shu-Chen Hsieh ◽

...

Keyword(s):

Mouse Model ◽

Tumor Growth ◽

Pancreatic Ductal Adenocarcinoma ◽

Ductal Adenocarcinoma ◽

M2 Macrophages ◽

Pdac Cell ◽

Cytochrome C Release ◽

In Vivo Evaluation ◽

Mesenchymal Transition

Octyl gallate (OG) is a common antioxidant and preservative safely used in food additive and cosmetics. In this study, OG exhibited an activity to induce apoptosis in pancreatic ductal adenocarcinoma (PDAC) cells. It induced BNIP3L level and facilitated physical associations of BNIP3L with Bcl-2 as well as Bcl-XL to set the mitochondrial Bax/Bak channels free for cytochrome c release. In addition, in vivo evaluation also showed that daily oral administration of OG was efficacious to prevent the tumor growth of PDAC cell grafts. Considering PDAC is a desmoplastic tumor consisting of many cancer-associated fibroblasts (CAFs), we further evaluated the efficacy of OG in a CAFs-involved PDAC mouse model. Endothelial-to-mesenchymal transition (EndoMT) is an important source of CAFs. The mix of EndoMT-derived CAFs with PDAC cell grafts significantly recruited myeloid-derived macrophages but prevented immune T cells. HSP90α secreted by EndoMT-derived CAFs further induced macrophage M2-polarization and more HSP90α secretion to expedite PDAC tumor growth. OG exhibited its potent efficacy against the tumor growth, M2-macrophages, and serum HSP90α level in the EndoMT-involved PDAC mouse model. CD91 and TLR4 are cell-surface receptors for extracellular HSP90α (eHSP90α). OG blocked eHSP90α–TLR4 ligation and, thus, prevented eHSP90α-induced M2-macrophages and more HSP90α secretion from macrophages and PDAC cells.

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Usp9x Promotes Survival in Human Pancreatic Cancer and Its Inhibition Suppresses Pancreatic Ductal Adenocarcinoma In Vivo Tumor Growth

Neoplasia ◽

10.1016/j.neo.2017.11.007 ◽

2018 ◽

Vol 20 (2) ◽

pp. 152-164 ◽

Cited By ~ 7

Author(s):

Anupama Pal ◽

Michele Dziubinski ◽

Marina Pasca Di Magliano ◽

Diane M. Simeone ◽

Scott Owens ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Growth ◽

Pancreatic Ductal Adenocarcinoma ◽

Human Pancreatic Cancer ◽

Ductal Adenocarcinoma

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283. Targeted Delivery of C/EBPα-Small Activation RNA (saRNA) by RNA Aptamer Inhibits the Growth of Pancreatic Ductal Adenocarcinoma (PDAC) In Vivo

Molecular Therapy ◽

10.1016/s1525-0016(16)33892-8 ◽

2015 ◽

Vol 23 ◽

pp. S113

Author(s):

Sorah Yoon ◽

Kai-Wen Huang ◽

Paul Mintz ◽

Nagy Habib ◽

John J. Rossi

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Targeted Delivery ◽

Ductal Adenocarcinoma ◽

Rna Aptamer

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780. The Bi-Functional RNA Aptamers Inhibit Pancreatic Ductal Adenocarcinoma (PDAC) Growth In Vivo

Molecular Therapy ◽

10.1016/s1525-0016(16)35793-8 ◽

2014 ◽

Vol 22 ◽

pp. S301

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Rna Aptamers ◽

Ductal Adenocarcinoma ◽

Functional Rna

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OXCT1 Enhances Gemcitabine Resistance Through NF-κB Pathway in Pancreatic Ductal Adenocarcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.698302 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jinsheng Ding ◽

Hui Li ◽

Yang Liu ◽

Yongjie Xie ◽

Jie Yu ◽

...

Keyword(s):

Tumor Growth ◽

Pancreatic Ductal Adenocarcinoma ◽

Signaling Pathway ◽

Cell Lines ◽

Bioinformatics Analysis ◽

Gene Set Enrichment Analysis ◽

Ductal Adenocarcinoma ◽

Pdac Cell ◽

Coa Transferase

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a type of malignant tumor with a five-year survival rate of less than 10%. Gemcitabine (GEM) is the most commonly used drug for PDAC chemotherapy. However, a vast majority of patients with PDAC develop resistance after GEM treatment.MethodsWe screened for GEM resistance genes through bioinformatics analysis. We used immunohistochemistry to analyze 3-oxoacid CoA-transferase 1 (OXCT1) expression in PDAC tissues. The survival data were analyzed using the Kaplan–Meier curve. The expression levels of the genes related to OXCT1 and the NF-κB signaling pathway were quantified using real−time quantitative PCR and western blot analyses. We performed flow cytometry to detect the apoptosis rate. Colony formation assay was performed to measure the cell proliferation levels. The cytotoxicity assays of cells were conducted using RTCA. The downstream pathway of OXCT1 was identified via the Gene Set Enrichment Analysis. Tumor growth response to GEM in vivo was also determined in mouse models.ResultsBioinformatics analysis revealed that OXCT1 is the key gene leading to GEM resistance. Patients with high OXCT1 expression exhibited short relapse-free survival under GEM treatment. OXCT1 overexpression in PDAC cell lines exerted inhibitory effect on apoptosis after GEM treatment. However, the down-regulation of OXCT1 showed the opposite effect. Blocking the NF-κB signaling pathway also reduced GEM resistance of PDAC cells. Tumor growth inhibition induced by GEM in vivo reduced after OXCT1 overexpression. Moreover, the effect of OXCT1 on GEM refractoriness in PDAC cell lines was reversed through using an NF-κB inhibitor.ConclusionOXCT1 promoted GEM resistance in PDAC via the NF-κB signaling pathway both in vivo and in vitro. Our results suggest that OXCT1 could be used as a potential therapeutic target for patients with PDAC.

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Nucleolin Targeting by N6L Inhibits Wnt/β-Catenin Pathway Activation in Pancreatic Ductal Adenocarcinoma

Cancers ◽

10.3390/cancers13122986 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2986

Author(s):

Fabio Raineri ◽

Sandrine Bourgoin-Voillard ◽

Mélissande Cossutta ◽

Damien Habert ◽

Matteo Ponzo ◽

...

Keyword(s):

Tumor Growth ◽

Pancreatic Ductal Adenocarcinoma ◽

Mouse Models ◽

Wnt Pathway ◽

The Other ◽

Ductal Adenocarcinoma ◽

Loss Of Function ◽

Tumor Vessels ◽

Pathway Activation

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and resistant cancer with no available effective therapy. We have previously demonstrated that nucleolin targeting by N6L impairs tumor growth and normalizes tumor vessels in PDAC mouse models. Here, we investigated new pathways that are regulated by nucleolin in PDAC. We found that N6L and nucleolin interact with β-catenin. We found that the Wnt/β-catenin pathway is activated in PDAC and is necessary for tumor-derived 3D growth. N6L and nucleolin loss of function induced by siRNA inhibited Wnt pathway activation by preventing β-catenin stabilization in PDAC cells. N6L also inhibited the growth and the activation of the Wnt/β-catenin pathway in vivo in mice and in 3D cultures derived from MIA PaCa2 tumors. On the other hand, nucleolin overexpression increased β-catenin stabilization. In conclusion, in this study, we identified β-catenin as a new nucleolin interactor and suggest that the Wnt/β-catenin pathway could be a new target of the nucleolin antagonist N6L in PDAC.

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