scholarly journals YAP Inhibition by Nuciferine via AMPK-Mediated Downregulation of HMGCR Sensitizes Pancreatic Cancer Cells to Gemcitabine

Biomolecules ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 620 ◽  
Author(s):  
Ling Zhou ◽  
Qiaoyun Wang ◽  
Han Zhang ◽  
Youjie Li ◽  
Shuyang Xie ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Therapeutic Strategy ◽  
Cultured Cells ◽  
Raw Material ◽  
Mechanism Study ◽  
Aporphine Alkaloid ◽  
Pancreatic Cancer Cells ◽  
Lotus Leaves ◽  
Coa Reductase ◽  
Gemcitabine Treatment

Nuciferine, a major aporphine alkaloid constituent of lotus leaves, is a raw material for obesity treatment. Extensive studies have revealed that obesity is associated with pancreatic cancer (PC). However, it has not been clarified whether nuciferine could be used in PC treatment or prevention. Here, we show that nuciferine could enhance the sensitivity of PC cells to gemcitabine in both cultured cells and the xenograft mouse model. The mechanism study demonstrated that nuciferine induced YAP Ser127 phosphorylation [pYAP(Ser127)] through AMPK-mediated 3-hydroxy-3-methyl-glutaryl-coA reductase (HMGCR) downregulation. Remarkably, wild-type YAP overexpression or YAP Ser127 mutant could resist to nuciferine and no longer sensitize PC cells to gemcitabine. Knockdown of AMPK attenuated pYAP(Ser127) induced by nuciferine. Moreover, knockdown of AMPK reversed nuciferine-mediated HMGCR downregulation. Notably, HMGCR inhibiting could restrain YAP by phosphorylation Ser 127, and therefore enhance the efficiency of gemcitabine in PC cells. In line with this consistent, overexpression of HMGCR reduced growth inhibition caused by nuciferine and/or gemcitabine treatment in PC cells. In summary, these results provide an effective supplementary agent and suggest a therapeutic strategy to reduce gemcitabine resistance in PC.

Enhancing responsiveness of pancreatic cancer cells to gemcitabine treatment under hypoxia by heme oxygenase-1 inhibition

2019 ◽  
Vol 207 ◽  
pp. 56-69 ◽  
Author(s):  
Maher Y. Abdalla ◽  
Iman M. Ahmad ◽  
Satyanarayana Rachagani ◽  
Kasturi Banerjee ◽  
Christopher M. Thompson ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Heme Oxygenase ◽  
Heme Oxygenase 1 ◽  
Pancreatic Cancer Cells ◽  
Gemcitabine Treatment

W1761 Genetic Expression Profile Suggesting Synergy Between Omega-3 Fatty Acids and Gemcitabine Treatment On Pancreatic Cancer Cells

2009 ◽  
Vol 136 (5) ◽  
pp. A-936
Author(s):  
Anthony Razzak ◽  
Justin Hering ◽  
Abdul Saied ◽  
Anthony Bais ◽  
Ponnandai Somasundar ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Fatty Acids ◽  
Cancer Cells ◽  
Expression Profile ◽  
Omega 3 Fatty Acids ◽  
Omega 3 ◽  
Genetic Expression ◽  
Pancreatic Cancer Cells ◽  
Gemcitabine Treatment

scholarly journals MiR-20a-5p regulates gemcitabine chemosensitivity by targeting RRM2 in pancreatic cancer cells and serves as a predictor for gemcitabine-based chemotherapy

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Huimin Lu ◽  
Shan Lu ◽  
Dujiang Yang ◽  
Ling Zhang ◽  
Jun Ye ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Luciferase Reporter ◽  
Luciferase Reporter Gene ◽  
Significant Discrepancy ◽  
Luciferase Reporter Gene Assay ◽  
Gemcitabine Resistance ◽  
Pancreatic Cancer Cells ◽  
Gene Assay ◽  
Long Time ◽  
Gemcitabine Treatment

Abstract Ribonucleotide reductase subunit M2 (RRM2) acts as an important gemcitabine resistance-related gene in pancreatic cancer (PC). Here, we aimed to investigate the potential microRNA that regulates gemcitabine chemosensitivity by targeting RRM2 and explores the clinical significance of candidate miRNA in PC. MTT assay and Western blot analysis revealed that long-time gemcitabine treatment in PC cells induced drug resistance and RRM2 increase, and silence of RRM2 blocked gemcitabine resistance. Among the predicted eight RRM2-related microRNAs, the expression of miR-20a-5p showed the most significant discrepancy between gemcitabine-resistant cells and parental cells. Furthermore, the Dual-Luciferase reporter gene assay indicated that miR-20a-5p directly targeted RRM2 3′UTR, thus inhibited expression of RRM2 and overcame gemcitabine resistance of PC cells. Retrospective study suggested that plasma miR-20a-5p level was correlated with gemcitabine resistance in PC patient. ROC curve showed that miR-20a-5p abundant level might predict gemcitabine resistance with an AUC of 89% (P<0.0001). Additionally, the PFS of patients with high and low expression levels miR-20a-5p was 2.8 and 4.5 months (P<0.001), respectively. Taken together, our results suggests that miR-20a-5p regulated gemcitabine chemosensitivity by targeting RRM2 in PC cells and could serve as a predictor for predicting the efficacy of gemcitabine-based chemotherapy in first-line treatment of PC patients.

Enhanced antitumor effect via combination of triptolide with 5-fluorouracil in pancreatic cancer cell lines.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 352-352 ◽  
Author(s):  
Wei Wang
Keyword(s):  
Pancreatic Cancer ◽  
Therapeutic Effect ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Advanced Pancreatic Cancer ◽  
Cancer Cell Lines ◽  
Human Pancreatic Cancer ◽  
Mechanism Study ◽  
Pancreatic Cancer Cells

352 Background: Pancreatic cancer is one of the most aggressive types of cancer, and lack of effective treatment results in a very low 6-month survival rate. This study aims to explore the enhancement of therapeutic effect on human pancreatic cancer cell lines (AsPC-1, MiaPaCa-2 and PANC-1) via combination of triptolide (TPL),derived from the herb Tripterygium wilfordii, and 5-fluorouracil (5-FU). Methods: Cell proliferation was measured by MTT, apoptotic cells were assessed by flow cytometry and western blot for cleaved caspase-8, 9, 3 and PARP. To explore the role of nuclear factor kappaB (NF-kB) activity in pancreatic cancer cell lines, AsPC-1/IkBaM and PANC-1/IkBaM cells (NF-kB activity of AsPC-1 and PANC-1 cells was silenced by IkB-a mutation) were treated with TPL plus 5-FU. NF-kB activity was determined by electrophoretic mobility shift assay. Results: TPL demonstrated toxicity on three pancreatic cancer cell lines with the IC50 of 25-40 nM. The combination of TPL (IC30 concentration) and 5-FU enhanced the cytotoxicity significantly compared to not only 5-FU alone but also Gemcitabine (the first line drug for advanced pancreatic cancer) alone. Combination index (CI) indicated the effect of TPL plus 5-FU was highly synergistic. Furthermore, pancreatic cancer cells treated with TPL plus 5-FU exhibited increased apoptosis, as evidenced by stronger Annexin V/ PI staining, higher levels of pro-apoptotic proteins including cleaved caspases and activated PARP compared to cells treated with TPL or 5-FU or Gemcitabine alone. In the mechanism study, AsPC-1/IkBaM and PANC-1/IkBaM cells showed more resistance to enhanced apoptosis induced by TPL plus 5-FU compared to wild-type cells. It indicated the enhanced effect of TPL was related with NF-kB activity. Conclusions: 1) TPL has a potent therapeutic effect on pancreatic cancer cell lines; 2) the combination of TPL with 5-FU enhances the therapeutic effect which is more powerful than Gemcitabine in vitro, low concentration of TPL showed high synergistic effect with 5-FU; 3) the inhibitory effect of TPL plus 5-FU on pancreatic cancer is mediated by the induction of apoptosis and TPL enhanced the apoptosis via inhibition of NF-kB activity.

Abstract 4673: A novel way to sensitize pancreatic cancer cells for gemcitabine treatment

2016 ◽  
Author(s):  
Jingwu Xie ◽  
Dongsheng Gu ◽  
Xiaoli Zhang ◽  
Yanfei Jia ◽  
Gabi Chiorean
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Pancreatic Cancer Cells ◽  
Gemcitabine Treatment

scholarly journals An engineered ligand trap inhibits leukemia inhibitory factor as pancreatic cancer treatment strategy

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Sean A. Hunter ◽  
Brianna J. McIntosh ◽  
Yu Shi ◽  
R. Andres Parra Sperberg ◽  
Chie Funatogawa ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Animal Models ◽  
Cancer Treatment ◽  
Leukemia Inhibitory Factor ◽  
Therapeutic Strategy ◽  
Inhibitory Factor ◽  
Wild Type ◽  
High Affinity ◽  
Mediated Effects ◽  
Pancreatic Cancer Cells

AbstractLeukemia inhibitory factor (LIF), a cytokine secreted by stromal myofibroblasts and tumor cells, has recently been highlighted to promote tumor progression in pancreatic and other cancers through KRAS-driven cell signaling. We engineered a high affinity soluble human LIF receptor (LIFR) decoy that sequesters human LIF and inhibits its signaling as a therapeutic strategy. This engineered ‘ligand trap’, fused to an antibody Fc-domain, has ~50-fold increased affinity (~20 pM) and improved LIF inhibition compared to wild-type LIFR-Fc, potently blocks LIF-mediated effects in pancreatic cancer cells, and slows the growth of pancreatic cancer xenograft tumors. These results, and the lack of apparent toxicity observed in animal models, further highlights ligand traps as a promising therapeutic strategy for cancer treatment.

scholarly journals Pentoxifylline and pirfenidone sensitize pancreatic cancer cells to gemcitabine treatment

2020 ◽  
Author(s):  
M. Helena Vasconcelos ◽  
Cristina Xavier ◽  
Inês Castro ◽  
Hugo Caires ◽  
Dylan Ferreira ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Pancreatic Cancer Cells ◽  
Gemcitabine Treatment

scholarly journals Harmine suppresses the proliferation of pancreatic cancer cells and sensitizes pancreatic cancer to gemcitabine treatment

2019 ◽  
Vol Volume 12 ◽  
pp. 4585-4593 ◽  
Author(s):  
Lin-wen Wu ◽  
Jian-kang Zhang ◽  
Mingjun Rao ◽  
Zuo-yan Zhang ◽  
Hua-jian Zhu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Pancreatic Cancer Cells ◽  
Gemcitabine Treatment
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