scholarly journals Pharmacological Inhibition and Genetic Knockdown of Exchange Protein Directly Activated by cAMP 1 Reduce Pancreatic Cancer Metastasis In Vivo

2014 ◽  
Vol 87 (2) ◽  
pp. 142-149 ◽  
Author(s):  
Muayad Almahariq ◽  
Celia Chao ◽  
Fang C. Mei ◽  
Mark R. Hellmich ◽  
Igor Patrikeev ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Metastasis ◽  
Pharmacological Inhibition ◽  
Exchange Protein

scholarly journals A novel in vitro model of metastasis supporting passive shedding hypothesis from murine pancreatic cancer Panc-02

2019 ◽  
Vol 71 (5) ◽  
pp. 989-1002
Author(s):  
M. P. Krzykawski ◽  
R. Krzykawska ◽  
M. Paw ◽  
J. Czyz ◽  
J. Marcinkiewicz
Keyword(s):  
Pancreatic Cancer ◽  
Cell Line ◽  
Cancer Metastasis ◽  
Metastatic Potential ◽  
Blood Stream ◽  
Culture Surface ◽  
Vitro Model ◽  
In Vitro Cell Cultures

Abstract Cancer metastasis is believed to happen through active intravasation but there might be also another way to metastasize. According to passive shedding hypothesis, proposed by Munn et al., tumor cells detach from the tumor mass and passively shed to blood stream through leaky blood vessels. We propose a novel In Vitro Migrational Selection (IVMS) assay that enables the pre-selection of invasive pancreatic cancer Panc-02 cells and create a model of passive shedding. We established invasive sub-cell line of murine pancreatic cancer Panc-02 cells (refered to as Panc02-RS), which exhibited higher metastatic potential in vivo and at the same time decrease in vitro migratory skills, comparing to the initial Panc-02 cell line. In in vitro cell cultures Panc-02 spontaneously detached from the cell culture surface and later reattached and colonized new areas. We believe it can mimic the new way of metastasis, namely passive shedding. We concentrated on Panc-02 model but believe that IVMS might be used to create sub cell lines of many solid tumors to model passive shedding. Our results support the passive shedding hypothesis.

scholarly journals Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel

2021 ◽  
Author(s):  
Samriddhi Arora ◽  
Jyoti Tanwar ◽  
Nutan Sharma ◽  
Suman Saurav ◽  
Rajender K. Motiani
Keyword(s):  
Pancreatic Cancer ◽  
Survival Time ◽  
Cell Lines ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Mesenchymal Transition

Pancreatic cancer (PC) is one of the most lethal forms of cancers with 5-year mean survival rate of less than 10%. Most of the PC associated deaths are due to metastasis to secondary sites. Calcium (Ca2+) signaling plays a critical role in regulating hallmarks of cancer progression including cell proliferation, migration and apoptotic resistance. Store operated Ca2+ entry (SOCE) mediated by Orai1/2/3 channels is a highly regulated and ubiquitous pathway responsible for Ca2+ influx into non-excitable cells. In this study, we performed extensive bioinformatic analysis of publicly available datasets and observed that Orai3 expression is inversely associated with the mean survival time of PC patients. Orai3 expression analysis in a battery of PC cell lines corroborated its differential expression profile. We then carried out thorough Ca2+ imaging experiments in 6 PC cell lines and found that Orai3 forms a functional SOCE in PC cells. Our in vitro functional assays show that Orai3 regulates PC cell cycle progression, apoptosis and migration. Most importantly, our in vivo xenograft studies demonstrate a critical role of Orai3 in PC tumor growth and secondary metastasis. Mechanistically, Orai3 controls G1 phase progression, matrix metalloproteinase expression and epithelial-mesenchymal transition in PC cells. Taken together, this study for the first time reports that Orai3 drives aggressive phenotypes of PC cells i.e. migration in vitro and metastasis in vivo. Considering that Orai3 expression is inversely associated with the PC patients survival time, it appears to be a highly attractive therapeutic target.

scholarly journals The EGFR-HSF1 Axis Accelerates the Tumorigenesis of Pancreatic Cancer

2020 ◽  
Author(s):  
Weikun Qian ◽  
Ke Chen ◽  
Tao Qin ◽  
Ying Xiao ◽  
Li Jie ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Precancerous Lesions ◽  
Precancerous Lesion ◽  
3D Culture ◽  
Pancreatic Acinar Cell ◽  
Ductal Adenocarcinoma ◽  
Heat Shock Factor 1 ◽  
Pharmacological Inhibition

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant diseases because of its non-symptomatic tumorigenesis. We previous found heat shock factor 1 (HSF1) was critical for PDAC progression and the aim of this study was to clarified the mechanisms on early activation of HSF1 and its role in the pancreatic cancer tumorigenesis. Methods: The expression and location of HSF1 on human or mice pancreatic tissues were examined by immunohistochemically staining. We mainly used pancreatic acinar cell 3-dimensional (3D) culture and a spontaneous pancreatic precancerous lesion mouse model called LSL-KrasG12D/+; Pdx1-Cre (KC) (and pancreatitis models derived from KC mice) to explore the pro-tumorigenesis mechanisms of the HSF1 in vitro and in vivo. Bioinformatics and molecular experiments were used to explore the underlying mechanisms between HSF1 and EGFR. Results: In this study, we found that pharmacological inhibition of HSF1 slowed pancreatic cancer initiation and suppressed the pancreatitis-induced formation of pancreatic precancerous lesion. Next, bioinformatics analysis revealed the closely linked between HSF1 and epidermal growth factor receptor (EGFR) pathway and we also confirmed their parallel activation in pancreatic precancerous lesions. Besides, the pharmacological inhibition of EGFR suppressed the initiation of pancreatic cancer and the activation of HSF1 in vivo. Indeed, we demonstrated that the EGFR activation that mediated pancreatic cancer tumorigenesis was partly HSF1-dependent in vitro.Conclusion: Hence, we concluded that the EGFR-HSF1 axis promoted the initiation of pancreatic cancer.

scholarly journals The EGFR-HSF1 axis accelerates the tumorigenesis of pancreatic cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Weikun Qian ◽  
Ke Chen ◽  
Tao Qin ◽  
Ying Xiao ◽  
Jie Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Precancerous Lesions ◽  
Precancerous Lesion ◽  
3D Culture ◽  
Pancreatic Acinar Cell ◽  
Ductal Adenocarcinoma ◽  
Heat Shock Factor 1 ◽  
Pharmacological Inhibition

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant diseases because of its non-symptomatic tumorigenesis. We previous found heat shock factor 1 (HSF1) was critical for PDAC progression and the aim of this study was to clarified the mechanisms on early activation of HSF1 and its role in the pancreatic cancer tumorigenesis. Methods The expression and location of HSF1 on human or mice pancreatic tissues were examined by immunohistochemically staining. We mainly used pancreatic acinar cell 3-dimensional (3D) culture and a spontaneous pancreatic precancerous lesion mouse model called LSL-KrasG12D/+; Pdx1-Cre (KC) (and pancreatitis models derived from KC mice) to explore the pro-tumorigenesis mechanisms of the HSF1 in vitro and in vivo. Bioinformatics and molecular experiments were used to explore the underlying mechanisms between HSF1 and epidermal growth factor receptor (EGFR). Results In this study, we found that pharmacological inhibition of HSF1 slowed pancreatic cancer initiation and suppressed the pancreatitis-induced formation of pancreatic precancerous lesion. Next, bioinformatics analysis revealed the closely linked between HSF1 and EGFR pathway and we also confirmed their parallel activation in pancreatic precancerous lesions. Besides, the pharmacological inhibition of EGFR suppressed the initiation of pancreatic cancer and the activation of HSF1 in vivo. Indeed, we demonstrated that the EGFR activation that mediated pancreatic cancer tumorigenesis was partly HSF1-dependent in vitro. Conclusion Hence, we concluded that the EGFR-HSF1 axis promoted the initiation of pancreatic cancer.

scholarly journals Exchange Protein Directly Activated by cAMP (EPAC1) Promotes Pancreatic Cancer Metastasis

2015 ◽  
Vol 29 (S1) ◽  
Author(s):  
Fang Mei ◽  
Muayad Almahariq ◽  
Celia Chao ◽  
Mark Hellmich ◽  
Xiaodong Cheng
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Metastasis ◽  
Exchange Protein

scholarly journals Downregulated F-Box/LRR-Repeat Protein 7 Facilitates Pancreatic Cancer Metastasis by Regulating Snail1 for Proteasomal Degradation

2021 ◽  
Vol 12 ◽  
Author(s):  
Liang Tang ◽  
Meng Ji ◽  
Xing Liang ◽  
Danlei Chen ◽  
Anan Liu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Invasion ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Proteasomal Degradation ◽  
Human Pancreatic Cancer ◽  
Mesenchymal Transition ◽  
Repeat Protein ◽  
Panc1 Cell

Pancreatic cancer (PCa) is one of the most aggressive lethal malignancies, and cancer metastasis is the major cause of PCa-associated death. F-box/LRR-repeat protein 7 (FBXL7) regulates cancer metastasis and the chemosensitivity of human pancreatic cancer. However, the clinical significance and biological role of FBXL7 in PCa have been rarely studied. In this study, we found that the expression of FBXL7 was down-regulated in PCa tissues compared with tumor-adjacent tissues, and the low expression of FBXL7 was positively associated with cancer metastasis. Functionally, overexpression of FBXL7 attenuated PANC1 cell invasion, whereas FBXL7 silencing promoted BxPC-3 cell invasion. Forced expression of FBXL7 upregulated the expression of epithelial markers (e.g., E-cadherin) and repressed the expression of mesenchymal markers (e.g., N-cadherin and Vimentin), indicating that FBXL7 negatively regulated the epithelial-mesenchymal transition (EMT) of PCa cells. Furthermore, we identified that FBXL7 repressed the expression of Snail1, a crucial transcription factor of EMT. Mechanistically, FBXL7 bound to Snail1 and promoted its ubiquitination and proteasomal degradation. In vivo studies demonstrated that FBXL7 inhibition promotes PCa metastasis. Taken together, our findings demonstrate that FBXL7 knockdown could efficiently enhance PCa metastasis by regulating Snail1-dependent EMT.

scholarly journals The EGFR-HSF1 axis accelerates the tumorigenesis of pancreatic cancer

2020 ◽  
Author(s):  
Weikun Qian ◽  
Ke Chen ◽  
Tao Qin ◽  
Ying Xiao ◽  
Li Jie ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Precancerous Lesions ◽  
Precancerous Lesion ◽  
3D Culture ◽  
Pancreatic Acinar Cell ◽  
Ductal Adenocarcinoma ◽  
Heat Shock Factor 1 ◽  
Pharmacological Inhibition

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant diseases because of its non-symptomatic tumorigenesis. We previous found heat shock factor 1 (HSF1) was critical for PDAC progression and the aim of this study was to clarified the mechanisms on early activation of HSF1 and its role in the pancreatic cancer tumorigenesis. Methods: The expression and location of HSF1 on human or mice pancreatic tissues were examined by immunohistochemically staining. We mainly used pancreatic acinar cell 3-dimensional (3D) culture and a spontaneous pancreatic precancerous lesion mouse model called LSL-KrasG12D/+; Pdx1-Cre (KC) (and pancreatitis models derived from KC mice) to explore the pro-tumorigenesis mechanisms of the HSF1 in vitro and in vivo. Bioinformatics and molecular experiments were used to explore the underlying mechanisms between HSF1 and epidermal growth factor receptor (EGFR). Results: In this study, we found that pharmacological inhibition of HSF1 slowed pancreatic cancer initiation and suppressed the pancreatitis-induced formation of pancreatic precancerous lesion. Next, bioinformatics analysis revealed the closely linked between HSF1 and EGFR pathway and we also confirmed their parallel activation in pancreatic precancerous lesions. Besides, the pharmacological inhibition of EGFR suppressed the initiation of pancreatic cancer and the activation of HSF1 in vivo. Indeed, we demonstrated that the EGFR activation that mediated pancreatic cancer tumorigenesis was partly HSF1-dependent in vitro. Conclusion: Hence, we concluded that the EGFR-HSF1 axis promoted the initiation of pancreatic cancer.

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