Cordycepin induces apoptosis in human pancreatic cancer cells via the mitochondrial-mediated intrinsic pathway and suppresses tumor growth in vivo

Pancreatic cancer is a highly lethal disease with limited options for effective therapy and the lowest survival rate of all cancer forms. Therefore, a new, effective strategy for cancer treatment is in need. Previously, we found that a culture liquid extract of Cyathus striatus (CS) has a potent antitumor activity. In the present study, we aimed to investigate the effects of Cyathus striatus extract (CSE) on the growth of pancreatic cancer cells, both in vitro and in vivo. The proliferation assay (XTT), cell cycle analysis, Annexin/PI staining and TUNEL assay confirmed the inhibition of cell growth and induction of apoptosis by CSE. A Western blot analysis demonstrated the involvement of both the extrinsic and intrinsic apoptosis pathways. In addition, a RNAseq analysis revealed the involvement of the MAPK and P53 signaling pathways and pointed toward endoplasmic reticulum stress induced apoptosis. The anticancer activity of the CSE was also demonstrated in mice harboring pancreatic cancer cell line-derived tumor xenografts when CSE was given for 5 weeks by weekly IV injections. Our findings suggest that CSE could potentially be useful as a new strategy for treating pancreatic cancer.

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Nordihydroguaiaretic acid inhibits growth and induces apoptosis in human pancreatic cancer cells in vitro and in vivo

Gastroenterology ◽

10.1016/s0016-5085(00)84291-2 ◽

2000 ◽

Vol 118 (4) ◽

pp. A540

Author(s):

Thomas Seufferlein ◽

Michael J. Seckl ◽

Michael Beil ◽

Hardi Luhrs ◽

Roland M. Schmid ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Nordihydroguaiaretic Acid ◽

Human Pancreatic Cancer ◽

Pancreatic Cancer Cells

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m6A Methyltransferase METTL14-Mediated Upregulation of Cytidine Deaminase Promoting Gemcitabine Resistance in Pancreatic Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.696371 ◽

2021 ◽

Vol 11 ◽

Author(s):

Congjun Zhang ◽

Shuangyan Ou ◽

Yuan Zhou ◽

Pei Liu ◽

Peiying Zhang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Western Blotting ◽

Protein Level ◽

Cytidine Deaminase ◽

Critical Role ◽

Human Pancreatic Cancer ◽

Gemcitabine Resistance ◽

Pancreatic Cancer Cells

ObjectivePancreatic cancer is one of the most lethal human malignancies. Gemcitabine is widely used to treat pancreatic cancer, and the resistance to chemotherapy is the major difficulty in treating the disease. N6-methyladenosine (m6A) modification, which regulates RNA splicing, stability, translocation, and translation, plays critical roles in cancer physiological and pathological processes. METTL14, an m6A Lmethyltransferase, was found deregulated in multiple cancer types. However, its role in gemcitabine resistance in pancreatic cancer remains elusive.MethodsThe mRNA and protein level of m6A modification associated genes were assessed by QRT-PCR and western blotting. Then, gemcitabine‐resistant pancreatic cancer cells were established. The growth of pancreatic cancer cells were analyzed using CCK8 assay and colony formation assay. METTL14 was depleted by using shRNA. The binding of p65 on METTL14 promoter was assessed by chromatin immunoprecipitation (ChIP) assay. Protein level of deoxycytidine kinase (DCK) and cytidine deaminase (CDA) was evaluated by western blotting. In vivo experiments were conducted to further confirm the critical role of METTL14 in gemcitabine resistance.ResultsWe found that gemcitabine treatment significantly increased the expression of m6A methyltransferase METTL14, and METTL14 was up-regulated in gemcitabine-resistance human pancreatic cancer cells. Suppression of METTL14 obviously increased the sensitivity of gemcitabine in resistant cells. Moreover, we identified that transcriptional factor p65 targeted the promoter region of METTL14 and up-regulated its expression, which then increased the expression of cytidine deaminase (CDA), an enzyme inactivates gemcitabine. Furthermore, in vivo experiment showed that depletion of METTL14 rescue the response of resistance cell to gemcitabine in a xenograft model.ConclusionOur study suggested that METTL14 is a potential target for chemotherapy resistance in pancreatic cancer.

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Identification of phosphoenolpyruvate carboxykinase 1 as a potential therapeutic target for pancreatic cancer

Cell Death and Disease ◽

10.1038/s41419-021-04201-w ◽

2021 ◽

Vol 12 (10) ◽

Author(s):

Xiao-ren Zhu ◽

Shi-qing Peng ◽

Le Wang ◽

Xiao-yu Chen ◽

Chun-xia Feng ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Therapeutic Target ◽

Phosphoenolpyruvate Carboxykinase ◽

Human Pancreatic Cancer ◽

Migration And Invasion ◽

Potential Therapeutic Target ◽

Protein Levels ◽

Pancreatic Cancer Cells

AbstractPancreatic cancer is the third leading cause of cancer-related mortalities and is characterized by rapid disease progression. Identification of novel therapeutic targets for this devastating disease is important. Phosphoenolpyruvate carboxykinase 1 (PCK1) is the rate-limiting enzyme of gluconeogenesis. The current study tested the expression and potential functions of PCK1 in pancreatic cancer. We show that PCK1 mRNA and protein levels are significantly elevated in human pancreatic cancer tissues and cells. In established and primary pancreatic cancer cells, PCK1 silencing (by shRNA) or CRISPR/Cas9-induced PCK1 knockout potently inhibited cell growth, proliferation, migration and invasion, and induced robust apoptosis activation. Conversely, ectopic overexpression of PCK1 in pancreatic cancer cells accelerated cell proliferation and migration. RNA-seq analyzing of differentially expressed genes (DEGs) in PCK1-silenced pancreatic cancer cells implied that DEGs were enriched in the PI3K-Akt-mTOR cascade. In pancreatic cancer cells, Akt-mTOR activation was largely inhibited by PCK1 shRNA, but was augmented after ectopic PCK1 overexpression. In vivo, the growth of PCK1 shRNA-bearing PANC-1 xenografts was largely inhibited in nude mice. Akt-mTOR activation was suppressed in PCK1 shRNA-expressing PANC-1 xenograft tissues. Collectively, PCK1 is a potential therapeutic target for pancreatic cancer.

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Radiosensitivity of human pancreatic cancer cells in vitro and in vivo, and the effect of a new hypoxic cell sensitizer, doranidazole

Radiotherapy and Oncology ◽

10.1016/s0167-8140(00)00181-x ◽

2000 ◽

Vol 56 (2) ◽

pp. 265-270 ◽

Cited By ~ 27

Author(s):

Yuta Shibamoto ◽

Takeshi Kubota ◽

Ken-ichi Kishii ◽

Michihiko Tsujitani

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Human Pancreatic Cancer ◽

Hypoxic Cell ◽

Pancreatic Cancer Cells

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

Cancers ◽

10.3390/cancers10080254 ◽

2018 ◽

Vol 10 (8) ◽

pp. 254 ◽

Cited By ~ 5

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.

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Characterization of the Bystander Effect of Somatostatin Receptor sst2 After In Vivo Gene Transfer into Human Pancreatic Cancer Cells

Human Gene Therapy ◽

10.1089/hum.2005.16.1175 ◽

2005 ◽

Vol 16 (10) ◽

pp. 1175-1193 ◽

Cited By ~ 24

Author(s):

Nicolas Carrere ◽

Fabienne Vernejoul ◽

Anny Souque ◽

Amani Asnacios ◽

Nicole Vaysse ◽

...

Keyword(s):

Pancreatic Cancer ◽

Gene Transfer ◽

Cancer Cells ◽

Bystander Effect ◽

Somatostatin Receptor ◽

Human Pancreatic Cancer ◽

Pancreatic Cancer Cells ◽

In Vivo Gene Transfer

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Activation of glucagon-like peptide-1 receptor inhibits growth and promotes apoptosis of human pancreatic cancer cells in a cAMP-dependent manner

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00017.2014 ◽

2014 ◽

Vol 306 (12) ◽

pp. E1431-E1441 ◽

Cited By ~ 19

Author(s):

Hejun Zhao ◽

Rui Wei ◽

Liang Wang ◽

Qing Tian ◽

Ming Tao ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Human Pancreatic Cancer ◽

Dependent Manner ◽

Pancreatic Cancer Cells ◽

Tumor Tissues ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) promotes pancreatic β-cell regeneration through GLP-1 receptor (GLP-1R) activation. However, whether it promotes exocrine pancreas growth and thereby increases the risk of pancreatic cancer has been a topic of debate in recent years. Clinical data and animal studies published so far have been controversial. In the present study, we report that GLP-1R activation with liraglutide inhibited growth and promoted apoptosis in human pancreatic cancer cell lines in vitro and attenuated pancreatic tumor growth in a mouse xenograft model in vivo. These effects of liraglutide were mediated through activation of cAMP production and consequent inhibition of Akt and ERK1/2 signaling pathways in a GLP-1R-dependent manner. Moreover, we examined GLP-1R expression in human pancreatic cancer tissues and found that 43.3% of tumor tissues were GLP-1R-null. In the GLP-1R-positive tumor tissues (56.7%), the level of GLP-1R was lower compared with that in tumor-adjacent normal pancreatic tissues. Furthermore, the GLP-1R-positive tumors were significantly smaller than the GLP-1R-null tumors. Our study shows for the first time that GLP-1R activation has a cytoreductive effect on human pancreatic cancer cells in vitro and in vivo, which may help address safety concerns of GLP-1-based therapies in the context of human pancreatic cancer.

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