scholarly journals Augmenting nab-paclitaxel/gemcitabine standard chemotherapy response by merestinib, an inhibitor of c-MET, Axl and DDR signaling pathways, in preclinical pancreatic cancer models

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Eda Shi
Keyword(s):  
Cell Proliferation ◽  
Dose Level ◽  
Immunoblot Analysis ◽  
Ductal Adenocarcinoma ◽  
Tumor Growth Inhibition ◽  
Chemotherapy Response ◽  
Standard Chemotherapy ◽  
Medium Dose

Background and Hypothesis: Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies in Western countries. Nab-paclitaxel (NPT) plus gemcitabine (Gem) is the standard of care for PDAC leading to a dismal 8.5 months median survival. Aberrant signaling of c-MET, Axl and DDR have been reported in a variety of human cancers including PDAC. Merestinib (Mer) is a potent, smallmolecule inhibitor of these pathways. We evaluated the therapeutic efficacy of merestinib to enhance the antitumor response of standard chemotherapy in preclinical models of PDAC. Project Methods: Cell proliferation of PDAC-associated cells (AsPC-1, PANC-1 and fibroblasts) were evaluated by colorimetric WST-1 assay. Protein expression was determined by Western blot analysis. Tumor progression studies were performed in NOD/SCID mice. Results: In vitro studies demonstrated that both nab-paclitaxel plus gemcitabine and merestinib suppressed cell proliferation of PDAC epithelial cells and stromal cells. Importantly, the combination treatment demonstrated additive inhibitory effects. In AsPC-1 cells, at the medium dose level, NPT+Gem, Mer and NPT+Gem+Mer treatments inhibited cell proliferation by 53.9%, 13.5%, and 81.61%, respectively. In PANC-1 cells, at the highest dose level, inhibition in cell proliferation by NPT+Gem, Mer and NPT+Gem+Mer treatments was 53.6%, 3.7%, and 72.8%. In the PDAC-associated fibroblasts, at the medium dose level, NPT+Gem, Mer and NPT+Gem+Mer treatments inhibited growth by 55.3%, 58.0%, and 91.6%. Immunoblot analysis revealed that merestinib caused a decrease in the PI-3K-AKT signaling proteins and an increase in apoptosisrelated proteins cleaved PARP-1 or cleaved caspase-3 in PDAC cells either alone or in combination with nab-paclitaxel and gemcitabine. In vivo study to evaluate tumor growth inhibition effects of merestinib in a subcutaneous PDAC xenograft is currently ongoing. Conclusion: The antitumor effect of standard chemotherapy regimen can be significantly enhanced by the cMET/Axl/DDR pathway inhibitor merestinib, which may lead to clinically relevant therapeutic strategy to increased survival in PDAC patients.

scholarly journals Enhancing cytotoxic chemotherapy response through targeted BET bromodomain inhibition in preclinical pancreatic cancer models

2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Sandeep Singh ◽  
Ross McCauley ◽  
Johann R. Schwarz ◽  
Roderich Schwarz ◽  
Niranjan Awasthi
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Cytotoxic Chemotherapy ◽  
Ductal Adenocarcinoma ◽  
Chemotherapy Response ◽  
Standard Chemotherapy ◽  
Animal Survival ◽  
Bet Protein

Background and Hypothesis:   Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and the standard of care regimen, nab-paclitaxel (NPT) plus gemcitabine (Gem), leads to a dismal 8.5 months median survival. Targeted inhibition of Bromodomain and Extra-Terminal (BET) protein is currently under investigation for several cancers. We hypothesize that BET protein pathway inhibition by iBet-762 will enhance cytotoxic chemotherapy response in PDAC.  Experimental Design:  In vitro cell proliferation assays were performed using WST-1 reagent. Protein expressions were determined by Western Blot analysis. In vivo animal survival and tumor growth experiments were performed in NOD-SCID mice.   Results:  Inhibition in cell proliferation in human PDAC cells at 1 µM concentration in NPT+Gem, iBET-762, and NPT+Gem+iBet762 was 64%, 27%, 76% in AsPC-1; 43%, 13%, 69% in Panc-1; and 42%, 51%, 75% in MIA PaCa cells. iBET-762 decreased oncogenic proteins c-Myc, [Symbol]-catenin, Vimentin, and P-AKT while apoptosis related proteins such as cleaved PARP-1 and cleaved caspase-3 and cell cycle inhibitors proteins P21 & P27 were increased. In a peritoneal dissemination model, median animal survival compared to control (21 days) was increased after therapy with NPT+Gem (33 days, a 57% increase), iBet-762 (30 days, a 43% increase) and NPT+Gem+iBET-762 (44 days, a 110% increase). Effect of iBET-762 in combination with chemotherapy on local tumor growth is currently underway.    Conclusion and Potential Impact:   These findings suggest that the effects of standard chemotherapy can be enhanced through specific inhibition of BET proteins activity, and supports the clinical application of iBET-762 in combination with standard chemotherapy in PDAC patients.

scholarly journals KIF4A Regulates the Progression of Pancreatic Ductal Adenocarcinoma through Proliferation and Invasion

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Jing Chen ◽  
Cui-Cui Zhao ◽  
Fei-Ran Chen ◽  
Guo-Wei Feng ◽  
Fei Luo ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Disease Free Survival ◽  
High Expression ◽  
Ductal Adenocarcinoma ◽  
Migration And Invasion

Background. Pancreatic cancer is a malignant tumor of the digestive tract, which is difficult to diagnose and treat due to bad early diagnosis. We aimed to explore the role of kinesin superfamily 4A (KIF4A) in pancreatic ductal adenocarcinoma (PDAC). Methods. We first used the bioinformatic website to screen the data of pancreatic cancer in TCGA, and KIF4A protein was detected among the 86 specimens of patients in our hospital combined with clinic-pathological characteristics and survival analysis. KIF4A loss-expression cell lines were established by RNA interference (RNAi). In addition, we performed in vitro cell assays to detect the changes in cell proliferation, migration, and invasion. The proteins involved in the proliferation and metastasis of cancer cells were also detected by western blot. The above results could be proved in vivo. Further, the correlation between KIF4A and CDC5L was analyzed by TCGA and IHC data. Results. We first found a high expression of KIF4A in pancreatic cancer, suggesting a role of KIF4A in the development of pancreatic cancer. KIF4A was found to be differentially expressed ( P < 0.05 ) among the 86 specimens of patients in our hospital and was significantly associated with PDAC TNM stages and tumor size. High KIF4A expression also significantly worsened overall survival (OS) and disease-free survival rate (DFS) ( P < 0.05 , respectively). In addition, cell proliferation, migration, and invasion were inhibited by the KIF4A-shRNA group compared with the control ( P < 0.05 , respectively). In the end, knockdown of KIF4A could inhibit tumor development and metastasis in vivo. Further, the positive correlation between KIF4A and CDC5L existed, and KIF4A might promote pancreatic cancer proliferation by affecting CDC5L expression. Conclusion. In conclusion, the high expression level of KIF4A in PDAC was closely related to poor clinical and pathological status, lymphatic metastasis, and vascular invasion. KIF4A might be involved in promoting the development of PDAC in vitro and in vivo, which might be a new therapeutic target of PDAC.

scholarly journals FUS-induced circRHOBTB3 facilitates cell proliferation via miR-600/NACC1 mediated autophagy response in pancreatic ductal adenocarcinoma

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Taoyue Yang ◽  
Peng Shen ◽  
Qun Chen ◽  
Pengfei Wu ◽  
Hao Yuan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Cell Lines ◽  
Rna Binding ◽  
Ductal Adenocarcinoma ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Pdac Cell

Abstract Background Circular RNAs (circRNAs) are becoming a unique member of non-coding RNAs (ncRNAs) with emerging evidence of their regulatory roles in various cancers. However, with regards to pancreatic ductal adenocarcinoma (PDAC), circRNAs biological functions remain largely unknown and worth investigation for potential therapeutic innovation. Methods In our previous study, next-generation sequencing was used to identify differentially expressed circRNAs in 3 pairs of PDAC and adjacent normal tissues. Further validation of circRHOBTB3 expression in PDAC tissues and cell lines and gain-and-loss function experiments verified the oncogenic role of circRHOBTB3. The mechanism of circRHOBTB3 regulatory role was validated by pull-down assays, RIP, luciferase reporter assays. The autophagy response of PANC-1 and MiaPaca-2 cells were detected by mCherry-GFP-LC3B labeling and confocal microscopy, transmission electron microscopy and protein levels of LC3B or p62 via Western blot. Results circRHOBTB3 is highly expressed in PDAC cell lines and tissues, which also promotes PDAC autophagy and then progression in vitro and in vivo. Mechanistically, circRHOBTB3 directly binds to miR-600 and subsequently acts as a miRNA-sponge to maintain the expression level of miR-600-targeted gene NACC1, which facilitates the autophagy response of PDAC cells for adaptation of proliferation via Akt/mTOR pathway. Moreover, the RNA-binding protein FUS (FUS) directly binds to pre-RHOBTB3 mRNA to mediate the biogenesis of circRHOBTB3. Clinically, circRHOBTB3, miR-600 and NACC1 expression levels are correlated with the prognosis of PDAC patients and serve as independent risk factors for PDAC patients. Conclusions FUS-mediated circRHOBTB3 functions as a tumor activator to promote PDAC cell proliferation by modulating miR-600/NACC1/Akt/mTOR axis regulated autophagy.

Augmenting chemotherapy response through EMAP II combination in experimental pancreatic cancer.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 294-294
Author(s):  
N. Awasthi ◽  
M. A. Schwarz ◽  
P. L. Yen ◽  
R. Schwarz
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Median Survival ◽  
Chemotherapy Response ◽  
Local Tumor ◽  
Antitumor Effects ◽  
Antiproliferative Effects ◽  
Local Tumor Growth

294 Background: Gemcitabine (Gem), the most active drug for locally advanced, non-operable and metastatic PDAC, has limited benefits as single agent or in combination. Endothelial monocyte activating polypeptide II (EMAP, E) enhances Gem effects in PDAC. We evaluated the antitumor activities of EMAP in combination with doxorubicin (Dox) or docetaxel (DT) in PDAC. Methods: In vitro cell proliferation, protein expression and apoptosis were analyzed by WST-1 assay, Western blotting and FACS analysis. In vivo local tumor growth and animal survival experiments were performed in murine xenografts. Results: In vitro PDAC cell proliferation was not affected by EMAP, compared to a small inhibition by Dox, DT and Gem. EMAP combination to these agents did not increase the antiproliferative effects. In endothelial cells (ECs), EMAP, Dox, DT and Gem all inhibited proliferation (59, 79, 96 and 85% at 10 μM, respectively); addition of EMAP caused additive antiproliferative effects. In PDAC cells, no agent caused measurable apoptosis, but in ECs all agents either alone or in combination increased the apoptosis. In vivo, Dox, DT, Gem and EMAP all decreased local tumor growth, and addition of EMAP enhanced inhibitory effects of DT and Gem, but not of Dox (92, 63, 60, 42, 73, 85 and 68 % inhibition after Dox, DT, Gem, E, Dox+E, DT+E and Gem+E, respectively); DT followed by Gem led to 72% inhibition without EMAP, and to 99% with EMAP (p=0.001). Inhibition of intra-tumoral proliferative activity and increase of apoptotic index were enhanced in all EMAP combination groups. Compared to controls (median survival: 21 days), EMAP (20 d) had no, but Dox (31 d) and DT (35 d) had extended survival benefit. EMAP enhanced the DT effect (44 d, p=0.009) but not that of Dox (31 d, p=0.04). In a sequential therapy experiment, median survival after controls, Gem, DT, Gem followed by DT, DT followed by Gem, Gem+E, DT+E, Gem/DT+E and DT/Gem+E was 17, 25, 29, 39, 39, 28, 35, 34 and 41 days, respectively. Conclusions: The antiendothelial agent EMAP enhances antitumor effects of not just gemcitabine. Therefore, combination approaches with EMAP-like agents could render other drugs such as taxanes or their doublets sufficiently effective for clinical applications in PDAC therapy. No significant financial relationships to disclose.

scholarly journals The Effect of Triptolide-Loaded Exosomes on the Proliferation and Apoptosis of Human Ovarian Cancer SKOV3 Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Huan Liu ◽  
Ming Shen ◽  
De Zhao ◽  
Dan Ru ◽  
Yourong Duan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Water Solubility ◽  
Tumor Growth Inhibition ◽  
Anticancer Efficacy ◽  
Skov3 Cells ◽  
Cell Proliferation Inhibition ◽  
Proliferation And Apoptosis

Triptolide has been proven to possess anticancer efficacy; however, its application in the clinical practice was limited by poor water solubility, hepatotoxicity, and nephrotoxicity. In this study, a triptolide-loaded exosomes delivery system (TP-Exos) was constructed and its effects on the proliferation and apoptosis of SKOV3 cells in vitro and in vivo were observed. SKOV3-exosomes (SK-Exos) were collected by ultracentrifugation and ultrafiltration centrifugation. TP-Exos was constructed by sonication and ultrafiltration centrifugation. SK-Exos and TP-Exos were characterized by transmission electron microscopy, western blotting, nanoparticle-tracking analysis, and high-performance liquid chromatography. Cellular uptake of exosomes, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, bromodeoxyuridine (BrdU) cell proliferation assay, and cell apoptosis experiment were used to study the effect of TP-Exos on ovarian cancer in vitro. Tumor-targeting study of exosomes, monitoring the tumor volume of mice, and TdT-mediated dUTP Nick-End labeling (TUNEL) assay were used to evaluate the effect of TP-Exos on ovarian cancer in vivo. The toxicity of TP-Exos in vivo was evaluated by liver and kidney function and histopathology of major organs (heart, liver, spleen, lung, kidney, and ovary). The results revealed that TP-Exos not only have the general characteristics of exosomes but also have high drug encapsulation efficiency. Besides, PKH26 labeled exosomes (PKH26-Exos) could be uptaken by SKOV3 cells, and Dir labeled exosomes (Dir-Exos) could be enriched to the tumor site of tumor bearing mice. Furthermore, the cytotoxic and apoptotic effects on SKOV3 cells of TP-Exos were weaker than those of free TP, and tumor cell proliferation inhibition and tumor growth inhibition were stronger than that of free TP. Moreover, TP-Exos have toxic effect on liver and spleen. In conclusion, the TP-Exos could be a promising strategy for ovarian cancer, but they need to be further optimized to attenuate the damage to liver and spleen.

scholarly journals m6A demethylase ALKBH5 inhibits pancreatic cancer tumorigenesis by decreasing WIF-1 RNA methylation and mediating Wnt signaling

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Bo Tang ◽  
Yihua Yang ◽  
Min Kang ◽  
Yunshan Wang ◽  
Yan Wang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Target Genes ◽  
Treated Patient ◽  
Ductal Adenocarcinoma ◽  
Rna Modification ◽  
Migration And Invasion ◽  
Altered Expression

Abstract Background Pancreatic cancer is one of the most lethal types of cancer with extremely poor diagnosis and prognosis, and chemo-resistance remains a major challenge. The dynamic and reversible N6-methyladenosine (m6A) RNA modification has emerged as a new layer of epigenetic gene regulation. Methods qRT-PCR and IHC were applied to examine ALKBH5 levels in normal and pancreatic cancer tissues. Cancer cell proliferation and chemo-resistance were evaluated by clonogenic formation, chemosensitivity detection, and Western blotting assays. m6A-seq was performed to identify target genes. We evaluated the inhibitory effect of ALKBH5 in both in vivo and in vitro models. Results Here, we show that m6A demethylase ALKBH5 is downregulated in gemcitabine-treated patient-derived xenograft (PDX) model and its overexpression sensitized pancreatic ductal adenocarcinoma (PDAC) cells to chemotherapy. Decreased ALKBH5 levels predicts poor clinical outcome in PDAC and multiple other cancers. Furthermore, silencing ALKBH5 remarkably increases PDAC cell proliferation, migration, and invasion both in vitro and in vivo, whereas its overexpression causes the opposite effects. Global m6A profile revealed altered expression of certain ALKBH5 target genes, including Wnt inhibitory factor 1 (WIF-1), which is correlated with WIF-1 transactivation and mediation of the Wnt pathway. Conclusions Our work uncovers the tumor suppressive and chemo-sensitizing function for ALKBH5, which provides insight into critical roles of m6A methylation in PDAC.

scholarly journals 609 Combining bintrafusp alfa with abituzumab enhances suppression of the TGF-β signaling pathway

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A639-A639
Author(s):  
Feng Jiang ◽  
Hong Wang ◽  
Tsz-Lun Yeung ◽  
Guozhong Qin ◽  
Bo Marelli ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Culture Medium ◽  
Phase 1 ◽  
Xenograft Model ◽  
Human Tumor ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tumor Growth Inhibition

BackgroundBintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor fused to a human IgG1 antibody blocking PD-L1. The TGF-βRII moiety of bintrafusp alfa functions as a ”trap” to sequester active TGF-β but does not block TGF-β release from its latent form. Multiple mechanisms lead to the release of active TGF-β. Integrins control local activation of latent TGF-β stored in the extracellular matrix and cell-surface reservoirs in the tumor microenvironment (TME). Alpha v integrin mRNA expression is correlated with multiple TGF-β gene signatures. It has been shown that αvβ8 integrin mediates TGF-β activation without releasing it from the latent TGF-β complex, suggesting that the TGF-βRII moiety of bintrafusp alfa may be unable to sequester TGF-β activated by αvβ8 integrin. Therefore, we hypothesize that combining abituzumab, a pan–αv integrin antibody, with bintrafusp alfa may lead to enhanced suppression of TGF-β signaling.MethodsThe expression of αv and β6 integrin mRNA was determined by RNA sequencing of triple-negative breast cancer (TNBC) tumor samples from a phase 1 clinical trial of bintrafusp alfa and correlated with patient response to bintrafusp alfa. The combination of bintrafusp alfa and abituzumab was investigated in vitro and in vivo in a TGF-β–dependent human tumor model, Detroit 562. In this study, CellTiter-Glo 2.0 Assay measured cell proliferation in vitro and enzyme-linked immunosorbent assay measured the level of latency-associated protein (LAP). A TGF-β reporter cell line MDA-MB-231 measured the level of active TGF-β. Antitumor activity in vivo was evaluated via tumor growth of Detroit 562 xenograft model in SCID mice.ResultsIn TNBC, increased expression of αv and β6 integrin mRNA was associated with poor response to bintrafusp alfa, suggesting that TGF-β activated by αv integrin may not be blocked by bintrafusp alfa. In Detroit 562 cells, abituzumab increased LAP levels in the cell culture medium, confirming modulation of the TGF-β pathway. As a result, the amount of active TGF-β released into culture medium was reduced by abituzumab. In vitro, both abituzumab and bintrafusp alfa suppressed Detroit 562 cell proliferation, and the combination suppressed cell proliferation further. In vivo, the combination led to increased tumor growth inhibition of Detroit 562 xenograft tumors relative to either monotherapy, further supporting the potential of this combination.ConclusionsCollectively, these preclinical findings support clinical development of bintrafusp alfa and abituzumab combination therapy to maximally suppress TGF-β signaling in the TME.AcknowledgementsWe thank George Locke for his analysis of the RNAseq data.Ethics ApprovalThis study was approved by the Institutional Animal Care and Use Committee at EMD Serono, Inc.; approval number [17–008].

scholarly journals Long noncoding RNA Linc00337 functions as an E2F1 co-activator and promotes cell proliferation in pancreatic ductal adenocarcinoma

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Huakai Wang ◽  
Shiyong Yu ◽  
Huan Peng ◽  
Yijun Shu ◽  
Wenjie Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Ductal Adenocarcinoma ◽  
Regulation Mechanism ◽  
Clinical Value ◽  
Dismal Prognosis

Abstract Background Long noncoding RNA (lncRNA) Linc00337 has been implicated in lung, gastric, colorectal and esophageal squamous cell carcinoma progression via various mechanisms; however, its clinicopathological significance and role in pancreatic ductal adenocarcinoma (PDAC) progression remains largely unknown. Methods Multiple approaches such as bioinformatic analysis, Transfection, quantitative real-time-PCR, Western blotting, animal studies, RNA-immunoprecipitation (RIP), RNA-pulldown and RNA-Fluorescence in situ hybridization (RNA-FISH) and were utilized to explore the role of Linc00337 in PDAC. Results Here we identified Linc00337 is an oncogenic lncRNA during PDAC progression. We found that the expression of Linc00337 is elevated in PDAC tissues and the higher Linc00337 predicts dismal prognosis. Functionally, Linc00337 promotes PDAC cell proliferation and cell cycle transition both in vitro and in vivo. Mechanistically, Linc00337 binds to E2F1 and functions as an E2F1 coactivator to trigger the targets expression during PDAC progression. Conclusion Our results demonstrate a reciprocal regulation mechanism between Linc00337 and E2F1 in PDAC progression and report the clinical value of Linc00337 for PDAC prognosis and treatment.

scholarly journals SonoVue® vs. Sonazoid™ vs. Optison™: Which Bubble Is Best for Low-Intensity Sonoporation of Pancreatic Ductal Adenocarcinoma?

Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 98
Author(s):  
Spiros Kotopoulis ◽  
Mihaela Popa ◽  
Mireia Mayoral Safont ◽  
Elisa Murvold ◽  
Ragnhild Haugse ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Cancer Cell ◽  
Type Equation ◽  
Ultrasound Contrast Agents ◽  
Ductal Adenocarcinoma ◽  
Great Promise ◽  
Tumor Growth Inhibition ◽  
Ultrasound Parameters

The use of ultrasound and microbubbles to enhance therapeutic efficacy (sonoporation) has shown great promise in cancer therapy from in vitro to ongoing clinical studies. The fastest bench-to-bedside translation involves the use of ultrasound contrast agents (microbubbles) and clinical diagnostic scanners. Despite substantial research in this field, it is currently not known which of these microbubbles result in the greatest enhancement of therapy within the applied conditions. Three microbubble formulations—SonoVue®, Sonazoid™, and Optison™—were physiochemically and acoustically characterized. The microbubble response to the ultrasound pulses used in vivo was simulated via a Rayleigh–Plesset type equation. The three formulations were compared in vitro for permeabilization efficacy in three different pancreatic cancer cell lines, and in vivo, using an orthotopic pancreatic cancer (PDAC) murine model. The mice were treated using one of the three formulations exposed to ultrasound from a GE Logiq E9 and C1-5 ultrasound transducer. Characterisation of the microbubbles showed a rapid degradation in concentration, shape, and/or size for both SonoVue® and Optison™ within 30 min of reconstitution/opening. Sonazoid™ showed no degradation after 1 h. Attenuation measurements indicated that SonoVue® was the softest bubble followed by Sonazoid™ then Optison™. Sonazoid™ emitted nonlinear ultrasound at the lowest MIs followed by Optison™, then SonoVue®. Simulations indicated that SonoVue® would be the most effective bubble using the evaluated ultrasound conditions. This was verified in the pre-clinical PDAC model demonstrated by improved survival and largest tumor growth inhibition. In vitro results indicated that the best microbubble formulation depends on the ultrasound parameters and concentration used, with SonoVue® being best at lower intensities and Sonazoid™ at higher intensities.

scholarly journals TMPRSS4 Promotes Cell Proliferation and Inhibits Apoptosis in Pancreatic Ductal Adenocarcinoma by Activating ERK1/2 Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Jianyou Gu ◽  
Wenjie Huang ◽  
Junfeng Zhang ◽  
Xianxing Wang ◽  
Tian Tao ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Signaling Pathway ◽  
Cellular Proliferation ◽  
Function Analysis ◽  
Ductal Adenocarcinoma ◽  
Pancreatic Cancer Cells

Transmembrane protease serine 4 (TMPRSS4) is upregulated in various kinds of human cancers, including pancreatic cancer. However, its biological function in pancreatic ductal adenocarcinoma (PDAC) remains unclear. In the current study, real-time qPCR, immunohistochemical staining, Western blotting, and database (Cancer Genome Atlas and Gene Expression) analysis revealed remarkable overexpression of TMPRSS4 in PDAC tissue as compared to non-tumor tissue. The TMPRSS4 overexpression was associated with poor prognosis of PDAC patients. Moreover, multivariate analysis revealed that TMPRSS4 serves as an independent risk factor in PDAC. We performed gain-and loss-of-function analysis and found that TMPRSS4 promotes cellular proliferation and inhibits apoptosis of PDAC cells both in vitro and in vivo. Furthermore, we showed that TMPRSS4 might promote cell proliferation and inhibit apoptosis through activating ERK1/2 signaling pathway in pancreatic cancer cells. These findings were validated by using ERK1/2 phosphorylation inhibitor SCH772984 both in vitro and in vivo. Taken together, this study suggests that TMPRSS4 is a proto-oncogene, which promotes initiation and progression of PDAC by controlling cell proliferation and apoptosis. Our findings indicate that TMPRSS4 could be a promising prognostic biomarker and a therapeutic target for the treatment of pancreatic cancer.

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