CDK9 is a prognostic marker and therapeutic target in pancreatic cancer

Despite recent advances in diagnosis and therapy, prognosis of pancreatic cancer still remains very poor. Besides valid prognostic markers, novel therapeutic approaches are urgently needed. The family of cyclin-dependent kinases comprises 20 kinases which contribute to malignancy by promoting proliferation, migration, invasion, and apoptotic resistance of cancer cells. In this work, we investigated the role of CDK9 in pancreatic cancer. Immunohistochemical analysis of CDK9 expression in tumor and normal tissue of pancreatic cancer patients revealed an overexpression of CDK9 in pancreatic cancer tissue. In addition, high CDK9 expression in tumor tissue is associated with significantly shortened survival, especially in well-differentiated tumors. Moreover, the therapeutic potential of selective CDK9 inhibition on pancreatic cancer cells was evaluated by analysis of cell viability, long-term survival, and induction of apoptosis and characterized by western blotting and flow cytometry. Pharmacological CDK9 inhibition by SNS-032 drastically reduced cell viability in pancreatic cancer cells and potently suppressed long-term survival. Analyzing the mechanism of action revealed that CDK9 inhibition induced apoptosis and cell cycle arrest in a time-dependent manner by suppression of anti-apoptotic proteins. Furthermore, CDK9 inhibition potently enhances the therapeutic effect of chemotherapeutics in pancreatic cancer cells. In conclusion, we identified CDK9 as a negative prognostic marker in pancreatic cancer. Furthermore, pharmacological CDK9 inhibition is a novel and promising therapeutic approach for pancreatic cancer.

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Norepinephrine enhances cell viability and invasion, and inhibits apoptosis of pancreatic cancer cells in a Notch‑1‑dependent manner

Oncology Reports ◽

10.3892/or.2018.6696 ◽

2018 ◽

Author(s):

Weikun Qian ◽

Shifang Lv ◽

Jie Li ◽

Ke Chen ◽

Zhengdong Jiang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Viability ◽

Cancer Cells ◽

Dependent Manner ◽

Notch 1 ◽

Pancreatic Cancer Cells

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Faculty Opinions recommendation of Protease-activated receptor-2 induces migration of pancreatic cancer cells in an extracellular ATP-dependent manner.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718053140.793503760 ◽

2015 ◽

Author(s):

Ivana Novak ◽

Andrea Giannuzzo

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Extracellular Atp ◽

Dependent Manner ◽

Pancreatic Cancer Cells ◽

Protease Activated Receptor 2

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A lack of postoperative complications after pancreatectomy contributes to the long-term survival of patients with pancreatic cancer

Pancreatology ◽

10.1016/j.pan.2019.06.012 ◽

2019 ◽

Vol 19 (5) ◽

pp. 686-694 ◽

Cited By ~ 3

Author(s):

Naoya Kasahara ◽

Hiroshi Noda ◽

Nao Kakizawa ◽

Takaharu Kato ◽

Fumiaki Watanabe ◽

...

Keyword(s):

Pancreatic Cancer ◽

Postoperative Complications ◽

Term Survival ◽

Long Term Survival

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Blocking IL-6/GP130 Signaling Inhibits Cell Viability/Proliferation, Glycolysis, and Colony Forming Activity in Human Pancreatic Cancer Cells

Current Cancer Drug Targets ◽

10.2174/1568009618666180430123939 ◽

2019 ◽

Vol 19 (5) ◽

pp. 417-427 ◽

Cited By ~ 4

Author(s):

Xiang Chen ◽

Jilai Tian ◽

Gloria H. Su ◽

Jiayuh Lin

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Cell Viability ◽

Cancer Cells ◽

Cancer Cell ◽

Pancreatic Cancer Cell ◽

Human Pancreatic Cancer ◽

Multiple Cancer ◽

Pancreatic Cancer Cells ◽

Stat3 Phosphorylation

Background:Elevated production of the pro-inflammatory cytokine interleukin-6 (IL-6) and dysfunction of IL-6 signaling promotes tumorigenesis and are associated with poor survival outcomes in multiple cancer types. Recent studies showed that the IL-6/GP130/STAT3 signaling pathway plays a pivotal role in pancreatic cancer development and maintenance.Objective:We aim to develop effective treatments through inhibition of IL-6/GP130 signaling in pancreatic cancer.Methods:The effects on cell viability and cell proliferation were measured by MTT and BrdU assays, respectively. The effects on glycolysis was determined by cell-based assays to measure lactate levels. Protein expression changes were evaluated by western blotting and immunoprecipitation. siRNA transfection was used to knock down estrogen receptor α gene expression. Colony forming ability was determined by colony forming cell assay.Results:We demonstrated that IL-6 can induce pancreatic cancer cell viability/proliferation and glycolysis. We also showed that a repurposing FDA-approved drug bazedoxifene could inhibit the IL-6/IL-6R/GP130 complexes. Bazedoxifene also inhibited JAK1 binding to IL-6/IL-6R/GP130 complexes and STAT3 phosphorylation. In addition, bazedoxifene impeded IL-6 mediated cell viability/ proliferation and glycolysis in pancreatic cancer cells. Consistently, other IL-6/GP130 inhibitors SC144 and evista showed similar inhibition of IL-6 stimulated cell viability, cell proliferation and glycolysis. Furthermore, all three IL-6/GP130 inhibitors reduced the colony forming ability in pancreatic cancer cells.Conclusion:Our findings demonstrated that IL-6 stimulates pancreatic cancer cell proliferation, survival and glycolysis, and supported persistent IL-6 signaling is a viable therapeutic target for pancreatic cancer using IL-6/GP130 inhibitors.

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A Case of Mucin-producing Pancreatic Cancer with Long-term Survival Following Operation.

The Japanese Journal of Gastroenterological Surgery ◽

10.5833/jjgs.25.2023 ◽

1992 ◽

Vol 25 (7) ◽

pp. 2023-2026

Author(s):

Takumi Tamura ◽

Keizo Chikaishi ◽

Hisao Wakabayashi ◽

Takashi Maeba ◽

Satoshi Tanaka

Keyword(s):

Pancreatic Cancer ◽

Term Survival ◽

Long Term Survival

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Mesoporous TiO2 Nanaoparticles Inhibits Malignant Pancreatic Cancer Cells Through STAT Pathway

Science of Advanced Materials ◽

10.1166/sam.2021.4091 ◽

2021 ◽

Vol 13 (9) ◽

pp. 1716-1723

Author(s):

Jie Li ◽

Chao Xu ◽

Yueyue Lu ◽

Yan Zhang ◽

Xiaoping Tan

Keyword(s):

Pancreatic Cancer ◽

Cell Viability ◽

Cancer Cells ◽

Inhibitory Effect ◽

Positive Control ◽

Control Group ◽

Blank Group ◽

Pancreatic Cancer Cells ◽

Experimental Group ◽

Stat Pathway

Nanoparticles are known to have recognition ability for targeted delivery, and are thus widely used in the treatments of diseases. Mesoporous nano-titanium dioxide (TiO2) nanoparticles have characteristics of nanomaterials and their porous structure with high surface area strengthens their drug-loading capacity and targeting ability. This study aimed to investigate the effect of mesoporous nano-TiO2 on pancreatic cancer cells and STAT pathway activity. Initially, we prepared mesoporous TiO2 nanoparticles that were characterized. Pancreatic cancer cells were co-cultured with mesoporous nano-TiO2 nanoparticles at different concentrations (0.1 μg/mL, 0.5 μg/mL, 1 μg/mL, 5 μg/mL, and 10 μg/mL) or 10 μg/mL nano-TiO2 (positive control group) or cells cultured alone (blank group). Cell viability was determined at several specific time points (24 h, 48 h, and 72 h). Transwell assay and scratching assay were conducted to determine the number of migrated and invaded cells. STAT3 and JAK2 expressions were examined by RT-qPCR and Western blot analysis. The prepared mesoporous nano-TiO2 exhibited sharp diffraction peaks with enhanced intensity and diffraction rings. STAT pathway was activated in pancreas cancer cells, which had more fluorescent cells than normal cells. The presence of mesoporous nano-TiO2 nanoparticles suppressed cancer cell viability and their inhibition rate increased with increased of nano-TiO2 concentration. The concentration of 10 μg/mL exhibited greatest inhibitory effect and 10 μg/mL mesoporous nano-TiO2 thus was chosen for experimental group. The width of the scratch in the experimental group (19.97±0.82 mm) was higher than in the blank group and positive control group (P < 0.05); 10 μg/mL mesoporous nano-TiO2 significantly decreased the number of invaded cells (71.97±17.84) and number of cell clones (156.91±31.03) (P < 0.05). The expression levels of STAT3 (0.41±0.06 μg/μL) and JAK2 (0.39±0.04 ug/ul) were diminished by treatment with mesoporous nano-TiO2. Mesoporous nano-TiO2 inhibits pancreatic cancer cell growth and STAT expression, as its inhibitory effect depends on its concentration. These findings might provide a novel insight into nanoparticle-based treatment for pancreatic cancer.

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Perioperative glucocorticoids are associated with improved long-term survival after pancreatic cancer surgery: A retrospective cohort study

10.21203/rs.3.rs-20131/v1 ◽

2020 ◽

Author(s):

Yun-Xiao Zhang ◽

Dong-Liang Mu ◽

Ke-Min Jin ◽

Xue-Ying Li ◽

Dong-Xin Wang

Keyword(s):

Pancreatic Cancer ◽

Cohort Study ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

Radical Surgery ◽

Radical Resection ◽

Cancer Surgery ◽

Term Survival ◽

Long Term Survival

Abstract Background Perioperative anesthetic management may affect long-term outcome after cancer surgery. This study aimed to investigate the effect of perioperative glucocorticoids on long-term survival in patients after radical resection for pancreatic cancer.Methods In this retrospective cohort study, patients who underwent radical resection for pancreatic cancer from January 2005 to December 2016 were recruited. Baseline and perioperative data including use of glucocorticoids for prevention of postoperative nausea and vomiting were collected. Patients were followed up for tumor recurrence and survival. The primary outcome was the overall survival (OS); the secondary outcome was the recurrence-free survival (RFS). A multivariable Cox proportional hazard model was used to analyze the influence of perioperative glucocorticoid use on OS and RFS after correction for confounding factors.Results A total of 215 patients after radical surgery for pancreatic cancer were included in the study; of these, 112 received perioperative glucocorticoids and 103 did not. Patients were followed up for a median of 74.0 months (95% confidence interval [CI] 68.3-79.7). Both OS and RFS were significantly longer in patients with glucocorticoids than in those without (for OS: median 19.7 months [95% CI 12.3-36.2] vs. 13.9 months [8.0-23.9], P=0.001; for RFS: 12.0 months [6.0-28.0] vs. 6.9 months [4.2-17.0], P=0.002). After correction for confounding factors, perioperative glucocorticoids were significantly associated with prolonged OS (HR 0.692, 95% CI 0.499-0.959, P=0.027) and RFS (HR 0.634, 95% CI 0.459-0.878, P=0.006).Conclusions Perioperative use of low-dose glucocorticoids may improve long-term survival in patients undergoing radical surgery for pancreatic cancer.

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