scholarly journals Accumulation of Extracellular Hyaluronan by Hyaluronan Synthase 3 Promotes Tumor Growth and Modulates the Pancreatic Cancer Microenvironment

2014 ◽  
Vol 2014 ◽  
pp. 1-15 ◽  
Author(s):  
Anne Kultti ◽  
Chunmei Zhao ◽  
Netai C. Singha ◽  
Susan Zimmerman ◽  
Ryan J. Osgood ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Plasma Membrane ◽  
Tumor Growth ◽  
Cancer Growth ◽  
Hyaluronan Synthases ◽  
Pancreatic Cancer Cells ◽  
Lung Cancer Sample ◽  
Related Proteins ◽  
E Cadherin

Extensive accumulation of the glycosaminoglycan hyaluronan is found in pancreatic cancer. The role of hyaluronan synthases 2 and 3 (HAS2, 3) was investigated in pancreatic cancer growth and the tumor microenvironment. Overexpression of HAS3 increased hyaluronan synthesis in BxPC-3 pancreatic cancer cells. In vivo, overexpression of HAS3 led to faster growing xenograft tumors with abundant extracellular hyaluronan accumulation. Treatment with pegylated human recombinant hyaluronidase (PEGPH20) removed extracellular hyaluronan and dramatically decreased the growth rate of BxPC-3 HAS3 tumors compared to parental tumors. PEGPH20 had a weaker effect on HAS2-overexpressing tumors which grew more slowly and contained both extracellular and intracellular hyaluronan. Accumulation of hyaluronan was associated with loss of plasma membrane E-cadherin and accumulation of cytoplasmicβ-catenin, suggesting disruption of adherens junctions. PEGPH20 decreased the amount of nuclear hypoxia-related proteins and induced translocation of E-cadherin andβ-catenin to the plasma membrane. Translocation of E-cadherin was also seen in tumors from a transgenic mouse model of pancreatic cancer and in a human non-small cell lung cancer sample from a patient treated with PEGPH20. In conclusion, hyaluronan accumulation by HAS3 favors pancreatic cancer growth, at least in part by decreasing epithelial cell adhesion, and PEGPH20 inhibits these changes and suppresses tumor growth.

scholarly journals Lysosomal retargeting of Myoferlin mitigates membrane stress to enable pancreatic cancer growth

2021 ◽  
Author(s):  
Suprit Gupta ◽  
Julian Yano ◽  
Htet Htwe Htwe ◽  
Hijai R. Shin ◽  
Zeynep Cakir ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Plasma Membrane ◽  
Membrane Damage ◽  
Membrane Integrity ◽  
Human Pancreatic Cancer ◽  
Cancer Growth ◽  
Membrane Repair ◽  
Pancreatic Cancer Cells ◽  
Plasma Membrane Repair

AbstractLysosomes must maintain integrity of their limiting membrane to ensure efficient fusion with incoming organelles and degradation of substrates within their lumen. Pancreatic cancer cells upregulate lysosomal biogenesis to enhance nutrient recycling and stress resistance, but whether dedicated programs for maintaining lysosomal membrane integrity facilitate pancreatic cancer growth is unknown. Using proteomic-based organelle profiling, we identify the Ferlin family plasma membrane repair factor, Myoferlin, as selectively and highly enriched on the membrane of pancreatic cancer lysosomes. Mechanistically, lysosome localization of Myoferlin is necessary and sufficient for maintenance of lysosome health and provides an early-acting protective system against membrane damage that is independent from the endosomal sorting complex required for transport (ESCRT)-mediated repair network. Myoferlin is upregulated in human pancreatic cancer, predicts poor survival, and its ablation severely impairs lysosome function and tumour growth in vivo. Thus, retargeting of plasma membrane repair factors enhances pro-oncogenic activities of the lysosome.

scholarly journals TGF-βRII Knock-down in Pancreatic Cancer Cells Promotes Tumor Growth and Gemcitabine Resistance. Importance of STAT3 Phosphorylation on S727

Cancers ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 254 ◽  
Author(s):  
Vincent Drubay ◽  
Nicolas Skrypek ◽  
Lucie Cordiez ◽  
Romain Vasseur ◽  
Céline Schulz ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Locally Advanced ◽  
Western World ◽  
Pancreatic Cancer Cells ◽  
Stat3 Phosphorylation ◽  
The Impact

Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers in the Western world because of a lack of early diagnostic markers and efficient therapeutics. At the time of diagnosis, more than 80% of patients have metastasis or locally advanced cancer and are therefore not eligible for surgical resection. Pancreatic cancer cells also harbour a high resistance to chemotherapeutic drugs such as gemcitabine that is one of the main palliative treatments for PDAC. Proteins involved in TGF-β signaling pathway (SMAD4 or TGF-βRII) are frequently mutated in PDAC (50–80%). TGF-β signalling pathway plays antagonistic roles during carcinogenesis by initially inhibiting epithelial growth and later promoting the progression of advanced tumors and thus emerged as both tumor suppressor and oncogenic pathways. In order to decipher the role of TGF-β in pancreatic carcinogenesis and chemoresistance, we generated CAPAN-1 and CAPAN-2 cell lines knocked down for TGF-βRII (first actor of TGF-β signaling). The impact on biological properties of these TGF-βRII-KD cells was studied both in vitro and in vivo. We show that TGF-βRII silencing alters tumor growth and migration as well as resistance to gemcitabine. TGF-βRII silencing also leads to S727 STAT3 and S63 c-Jun phosphorylation, decrease of MRP3 and increase of MRP4 ABC transporter expression and induction of a partial EMT phenotype. These markers associated with TGF-β signaling pathways may thus appear as potent therapeutic tools to better treat/manage pancreatic cancer.

shRNA-MEDIATED KNOCKDOWN OF CCK mRNA IN PANCREATIC CANCER CELLS DOES NOT ALTER IN VIVO TUMOR GROWTH

Pancreas ◽  
2008 ◽  
Vol 37 (4) ◽  
pp. 484
Author(s):  
G. Matters ◽  
C. McGovern ◽  
J. Harms ◽  
K. Markovic ◽  
K. Anson ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Pancreatic Cancer Cells

Effect of KRAS and P-STAT3 inhibition by SBT-100 on gemcitabine and pancreatic cancer growth in vivo.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15727-e15727
Author(s):  
Sunanda Singh ◽  
Genoveva Murillo ◽  
Avani Singh ◽  
Samara Singh ◽  
Meenakshi S Parihar ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Targeted Therapy ◽  
Western Blot ◽  
Cancer Cells ◽  
Mtt Assay ◽  
Blot Analysis ◽  
Cancer Growth ◽  
Pancreatic Cancers ◽  
Pancreatic Cancer Cells

e15727 Background: Over 90% of pancreatic cancers have KRAS mutations and hyper-expression of P-STAT3 oncoproteins, which if specifically targeted may help treatment of pancreatic cancers. Singh Biotechnology’s proprietary technology engineered SBT-100, a single domain antibody that is bispecific for KRAS & STAT3, which can cross the cell membranes and bind to these intracellular oncoproteins. Combining this targeted therapy with an established chemotherapy, such as gemcitabine, may improve patient’s response to treatment. Methods: Human pancreatic cancer cells (PANC-1 and BX-PC3) were used. Biacore assay demonstrates SBT-100 binding to KRAS, KRAS (G12D), and STAT3. Immunoprecipitation (IP) and western blot analysis confirmed binding to STAT3 by SBT-100. Pancreatic cancer cells were treated at varying doses of SBT-100 ranging from 0µg/ml to 200µg/ml ± gemcitabine, and after 72 hours growth inhibition was determined by a MTT assay. PANC-1 tumors were grown in athymic nude mice, divided into four groups and staged to a range of 100-150mm3 before treatment. Groups were: vehicle only, SBT-100, gemcitabine, and SBT-100 & gemcitabine. Animals received treatments for 14 days, then monitored for 7 days. Results: Biacore study shows SBT-100 binds KRAS with an affinity of 10-9M, KRAS (G12D) with 10-8M, and STAT3 with 10-8M. IP and western blot analysis demonstrates that SBT-100 binds P-STAT3. MTT assay demonstrates SBT-100 inhibits the growth of PANC-1 and BX-PC3 (p < 0.001). In PANC1 cells a combination of SBT-100 & gemcitabine demonstrates synergism in inhibiting growth of PANC-1, even at 1/8th the gemcitabine IC50 concentration. PANC-1 xenograft study demonstrates that combination therapy of SBT-100 & gemcitabine is superior to either SBT-100 or gemcitabine alone. Compared to the vehicle group, SBT-100 & gemcitabine is far superior (p < 0.001) and gives statistically significant suppression of pancreatic cancer growth in vivo. Conclusions: Targeted therapy for KRAS and P-STAT3 expressing tumors with SBT-100 & gemcitabine is synergistic for the treatment of pancreatic cancer. This study suggests that synergism maybe achieved with lower doses of gemcitabine, thereby reducing toxicity in patients.

scholarly journals Thyroxine promotes lung cancer growth in an orthotopic mouse model

2019 ◽  
Vol 26 (6) ◽  
pp. 565-574 ◽  
Author(s):  
S Latteyer ◽  
S Christoph ◽  
S Theurer ◽  
G S Hönes ◽  
K W Schmid ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Plasma Membrane ◽  
Thyroid Hormone ◽  
Mouse Model ◽  
Tumor Growth ◽  
Hormone Receptors ◽  
Cancer Growth ◽  
Orthotopic Mouse Model ◽  
Tumor Weight

Thyroid hormones are important for physiology and homeostasis. In addition to nuclear thyroid hormone receptors, the plasma membrane protein integrin αvβ3 has been recognized as a receptor for both thyroxine (T4) and triiodothyronine (T3). Here, we studied whether thyroid hormone promotes growth of murine lung cancer via αvβ3 in vivo. Murine Lewis lung carcinoma cells (3LL), stably transfected with luciferase, were injected into mouse lungs. Tumor growth in untreated mice was compared to hypothyroid mice and hypothyroid mice treated with T3 or T4 with or without the αvβ3 inhibitor 3,5,3′,5′-tetraiodothyroacetic acid (Tetrac). Tumor progression was determined by serial in vivo imaging of bioluminescence emitted from the tumor. Tumor weight was recorded at the end of the experiment. Neoangiogenesis was determined by immunohistochemistry for CD31. Tumor growth was reduced in hypothyroidism and increased by T4 treatment. Strikingly, only T4 but not T3 treatment promoted tumor growth. This T4 effect was abrogated by the αvβ3 inhibitor Tetrac. Tumor weight and neoangiogenesis were also significantly increased only in T4-treated mice. The T4 effect on tumor weight and neoangiogenesis was abolished by Tetrac. In vitro, T4 did not stimulate 3LL cell proliferation or signaling pathway activation. We conclude that T4 promotes lung cancer growth in this orthotopic mouse model. The tumor-promoting effect is mediated via the plasma membrane integrin αvβ3 and increased neoangiogenesis rather than direct stimulation of 3LL cells. These data suggest that such effects of levothyroxine may need to be considered in cancer patients on T4 substitution.

scholarly journals TFEB Supports Pancreatic Cancer Growth through the Transcriptional Regulation of Glutaminase

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 483
Author(s):  
Ji Hye Kim ◽  
Jinyoung Lee ◽  
Young-Ra Cho ◽  
So-Yeon Lee ◽  
Gi-Jun Sung ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Stress Responses ◽  
Significant Inhibition ◽  
Nutrient Sensing ◽  
Glutamine Metabolism ◽  
Cancer Growth ◽  
Autophagic Flux ◽  
Pancreatic Cancer Cells

Transcription factor EB (TFEB) is a master regulator of lysosomal function and autophagy. In addition, TFEB has various physiological roles such as nutrient sensing, cellular stress responses, and immune responses. However, the precise roles of TFEB in pancreatic cancer growth remain unclear. Here, we show that pancreatic cancer cells exhibit a significantly elevated TFEB expression compared with normal tissue samples and that the genetic inhibition of TFEB results in a significant inhibition in both glutamine and mitochondrial metabolism, which in turn suppresses the PDAC growth both in vitro and in vivo. High basal levels of autophagy are critical for pancreatic cancer growth. The TFEB knockdown had no significant effect on the autophagic flux under normal conditions but interestingly caused a profound reduction in glutaminase (GLS) transcription, leading to an inhibition of glutamine metabolism. We observed that the direct binding of TFEB to the GLS and TFEB gene promotors regulates the transcription of GLS. We also found that the glutamate supplementation leads to a significant recovery of the PDAC growth that had been reduced by a TFEB knockdown. Taken together, our current data demonstrate that TFEB supports the PDAC cell growth by regulating glutaminase-mediated glutamine metabolism.

scholarly journals Targeted Intervention of eIF4A1 Promotes EMT and Metastasis of Pancreatic Cancer Cells through c-MYC/miR-9 Signaling

2021 ◽  
Author(s):  
Yuchong Zhao ◽  
Yun Wang ◽  
Wei Chen ◽  
Shuya Bai ◽  
Wang Peng ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
The Cancer Genome Atlas ◽  
Mesenchymal Transition ◽  
Early Metastasis ◽  
Pancreatic Cancer Cells ◽  
Single Use ◽  
E Cadherin

Abstract Background: Due to the lack of effective interference options, early metastasis remains a major cause of pancreatic ductal adenocarcinoma (PDAC) recurrence and mortality. However, the molecular mechanism of early metastasis is largely unknown. We characterize the function of eukaryotic translation initiation factors (eIFs) in Pancreatic cancer cell epithelial mesenchymal-transition (EMT) and metastasis, to investigate whether it is effective to inhibit EMT and metastasis by joint interference of eIFs and downstream c-MYC. Methods: We used the data of The Cancer Genome Atlas (TCGA) and Genome Tissue Expression (GTEx) to analyze the expression level of eIF4A1 in PDAC tissues, and further validated in a microarray containing 53 PDAC samples. Expression regulation and pharmacological inhibition of eIF4A1/c-MYC was performed to determine their role in migration, invasion, and metastasis in pancreatic cancer cells in vitro and in vivo.Results: Elevated expression of eIF4A1 was positively correlated with lymph node infiltration, tumor size, and indicated a poor prognosis. eIF4A1 decreased E-cadherin expression through c-MYC/miR-9 axis. Ablation of eIF4A1 and c-MYC decreased the EMT and metastasis capabilities of pancreatic cancer cells. Upregulation of eIF4A1 could attenuate the inhibition of EMT and metastasis induced by c-MYC downregulation. Single-use of eIF4A1 inhibitor Rocaglamide (RocA) or c-MYC inhibitor Mycro3 and joint intervention all significantly the EMT level of pancreatic cancer cells in vitro. However, the efficiency and safety of RocA single-use were not inferior to joint use in vivo. Conclusion: The results demonstrated that overexpression of eIF4A1 downregulated E-cadherin through c-MYC/miR-9 axis, which promoted EMT and metastasis of pancreatic cancer cells. Despite the potential loop between eIF4A1 and c-MYC existing, RocA single strategy was a promising therapy for the inhibition of eIF4A1 induced PDAC metastasis.

scholarly journals Targeted intervention of eIF4A1 inhibits EMT and metastasis of pancreatic cancer cells via c-MYC/miR-9 signaling

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yuchong Zhao ◽  
Yun Wang ◽  
Wei Chen ◽  
Shuya Bai ◽  
Wang Peng ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
Mesenchymal Transition ◽  
Early Metastasis ◽  
Pancreatic Cancer Cells ◽  
E Cadherin

Abstract Background Owing to the lack of effective treatment options, early metastasis remains the major cause of pancreatic ductal adenocarcinoma (PDAC) recurrence and mortality. However, the molecular mechanism of early metastasis is largely unknown. We characterized the function of eukaryotic translation initiation factors (eIFs) in epithelial-mesenchymal-transition (EMT) and metastasis in pancreatic cancer cells to investigate whether eIFs and downstream c-MYC affect EMT and metastasis by joint interference. Methods We used The Cancer Genome Atlas (TCGA) and Genome Tissue Expression (GTEx) databases to analyze eIF4A1 expression in PDAC tissues and further validated the findings with a microarray containing 53 PDAC samples. Expression regulation and pharmacological inhibition of eIF4A1 and c-MYC were performed to determine their role in migration, invasion, and metastasis in pancreatic cancer cells in vitro and in vivo. Results Elevated eIF4A1 expression was positively correlated with lymph node infiltration, tumor size, and indicated a poor prognosis. eIF4A1 decreased E-cadherin expression through the c-MYC/miR-9 axis. Loss of eIF4A1 and c-MYC decreased the EMT and metastasis capabilities of pancreatic cancer cells, whereas upregulation of eIF4A1 attenuated the inhibition of EMT and metastasis induced by c-MYC downregulation. Treatment with the eIF4A1 inhibitor rocaglamide (RocA) or the c-MYC inhibitor Mycro3 either alone or in combination significantly decreased the expression level of EMT markers in pancreatic cancer cells in vitro. However, the efficiency and safety of RocA alone were not inferior to those of the combination treatment in vivo. Conclusion Overexpression of eIF4A1 downregulated E-cadherin expression through the c-MYC/miR-9 axis, which promoted EMT and metastasis of pancreatic cancer cells. Despite the potential feedback loop between eIF4A1 and c-MYC, RocA monotherapy is a promising treatment inhibiting eIF4A1-induced PDAC metastasis.

scholarly journals Long noncoding RNA SOX2OT promotes pancreatic cancer cell migration and invasion through destabilizing FUS protein via ubiquitination

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yan Wang ◽  
Xiong-Fei Zhang ◽  
Dong-Yan Wang ◽  
Yi Zhu ◽  
Lei Chen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Migration ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Pancreatic Cancer Cell ◽  
Cancer Cell Migration ◽  
Pancreatic Cancer Cells ◽  
Tumor Growth And Metastasis ◽  
Fus Protein

AbstractPancreatic cancer is a highly aggressive and lethal digestive system malignancy. Our previous studies revealed the correlation of high levels of lncRNA SOX2OT expression with patients’ poor survival outcomes, the promoting role of SOX2OT in proliferation and cycle progression of pancreatic cancer cells, and the in vivo binding of SOX2OT to RNA binding protein FUS, which destabilized the protein expression of FUS. However, the mechanism of SOX2OT binding and inhibiting FUS protein stability remains unclear. In this study, we performed RNA pull-down, cycloheximide-chase, and ubiquitination assays to determine the effect of SOX2OT on FUS ubiquitination, and explored the specific regulatory mechanism of SOX2OT–FUS axis in pancreatic cancer cell migration, invasion, in vivo tumor growth, and metastasis through RNA sequencing. We found that SOX2OT binds to FUS through its 5′ and 3′ regions, resulting in FUS ubiquitination and degradation. The SOX2OT–FUS regulatory axis promotes migration, invasion, tumor growth, and metastasis ability of pancreatic cancer cells. The in-depth elaboration of the SOX2OT–FUS regulatory axis in pancreatic cancer may clarify the mechanism of action of SOX2OT and provide new ideas for pancreatic cancer treatment.

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