PANC-1 Pancreatic Cancer Cells Research Articles

Effects of RXRα on proliferation and apoptosis of pancreatic cancer cells through TGF-β/Smad signaling pathway.

The aim of this study was to investigate the effects of retinoid X receptor α (RXRα) on the proliferation and apoptosis of pancreatic cancer cells through the transforming growth factor-β (TGF-β)/Smad signaling pathway. The expression of RXRα in pancreatic cancer tissues and para-carcinoma tissues was detected via immunohistochemistry. Human pancreatic cancer PANC-1 cells were cultured and treated with RXRα in vitro. The apoptosis rate of cells was detected via flow cytometry. Furthermore, changes in the protein expression level of TGF-β/Smad signaling pathway were detected via Western blotting. The protein expression level of RXRα in pancreatic cancer tissues was significantly higher than that of para-carcinoma tissues. RXRα significantly promoted the proliferation and inhibited the apoptosis of pancreatic cancer cells. Moreover, RXRα could also activate the TGF-β/Smad signaling pathway. RXRα promotes the proliferation and inhibits the apoptosis of pancreatic cancer cells through the TGF-β/Smad signaling pathway.

Thermal cycling-hyperthermia in combination with polyphenols, epigallocatechin gallate and chlorogenic acid, exerts synergistic anticancer effect against human pancreatic cancer PANC-1 cells.

Hyperthermia (HT) has shown feasibility and potency as an anticancer therapy. Administration of HT in the chemotherapy has previously enhanced the cytotoxicity of drugs against pancreatic cancer. However, the drugs used when conducting these studies are substantially conventional chemotherapeutic agents that may cause unwanted side effects. Additionally, the thermal dosage in the treatment of cancer cells could also probably harm the healthy cells. The purpose of this work was to investigate the potential of the two natural polyphenolic compounds, epigallocatechin gallate (EGCG) and chlorogenic acid (CGA), as heat synergizers in the thermal treatment of the PANC-1 cells. Furthermore, we have introduced a unique strategy entitled the thermal cycling-hyperthermia (TC-HT) that is capable of providing a maximum synergy and minimal side effect with the anticancer compounds. Our results demonstrate that the combination of the TC-HT and the CGA or EGCG markedly exerts the anticancer effect against the PANC-1 cells, while none of the single treatment induced such changes. The synergistic activity was attributed to the cell cycle arrest at the G2/M phase and the induction of the ROS-dependent mitochondria-mediated apoptosis. These findings not only represent the first in vitro thermal synergistic study of natural compounds in the treatment of pancreatic cancer, but also highlight the potential of the TC-HT as an alternative strategy in thermal treatment.

Coptisine suppresses proliferation and inhibits metastasis in human pancreatic cancer PANC-1 cells

The effects of coptisine against advanced stage of human pancreatic carcinoma PANC-1 cells was investigated in vitro. Coptisine (25–150 μM) treatment for 48 h caused dose-dependent cell growth inhibition by using CCK-8 assay. Additionally, coptisine was found to inhibit PANC-1 cells metastasis by the wound healing assay. Flow cytometry data indicated that coptisine (25–100 μM) exhibited dose-dependent G1 phase arrest and moderate reduction of S phase. Coptisine was also found to inhibit ERK phosphorylation and total ERK levels. Our research suggested that coptisine would be a potential therapeutic drug for the treatment of pancreatic cancer.

Regioselective synthesis and structures of anti-cancer 20(R)-ginsenoside Rg3 derivatives

Regioselective synthesis of three novel palmitates of 20(R)-ginsenoside Rg3 was accomplished via a facile strategy, along with complete assignment of their 1H and 13C NMR resonances by 1D and 2D NMR (1H-1H COSY, DEPT 135, HSQC, HMBC, and NOESY) techniques. The derivatives were tested for in vitro anti-proliferative activities against pancreatic cancer PANC-1 cells. Compounds 2, 3, and 4 exhibited more potent activity than did 20(R)-ginsenoside Rg3.

LncRNA CCAT1 enhances radiosensitivity of human pancreatic cancer cells PANC-1 by targeting miR-130b-3p

Objective To investigate the effect of lncRNA CCAT1 and miR-130b-3p on the radiosensitivity of human pancreatic cancer cells PANC-1. Methods Real-time PCR was used to detect the relative expression levels of CCAT1 and miR-130b-3p in pancreatic cancer tissues and cell lines including PANC-1 cells irradiated with 2 Gy X-rays. After silencing CCAT1 and/or inhibiting miR-130b-3p expression, cell apoptosis rate, Caspase 3 activity and cell survival were detected by flow cytometry, Caspase 3 activity detection kit and colony formation assay, respectively. Cell survival curve was stimulated by the multi-target single-hit model. Based on the starBase v2.0 online analysis, the luciferase reporter gene assay, RNA-binding protein immunoprecipitation assay (RIP) and Real-time PCR assay were applied to verify the relationship between CCAT1 and miR-130b-3p. Results CCAT1 expression was up-regulated (t=6.322-8.555, P<0.05), but miR-130b-3p expression was down-regulated (t=3.950-18.795, P<0.05) in the radiation-resistant pancreatic cancer tissues, pancreatic cancer cell lines and 2 Gy-irradiated PANC-1 cells. When the CCAT1 silenced PANC-1 cells were irradiated with 2 Gy, cell survival fraction decreased (t=2.929, 5.047, 5.234, 5.125, P<0.05), apoptosis rate and Caspase 3 activity increased (t=6.953, 6.836, P<0.05). CCAT1 could selectively regulate miR-130b-3p expression. Inhibition of miR-130b-3p expression could enhance PANC-1 cell survival (t=4.564, 6.736, 8.656, P<0.05), but reduced apoptosis rate (t=5.234, P<0.05) and Caspase 3 activity (t=10.440, P<0.05). Conclusions Silencing CCAT1 promotes the expression of miR-130b-3p and enhances radiosensitivity of PANC-1 cells. Key words: lncRNA CCAT1; miR-130b-3p; Pancreatic cancer; Radiosensitivity

GLI inhibitors overcome Erlotinib resistance in human pancreatic cancer cells by modulating E-cadherin

Inhibition of hedgehog (Hh) signalling pathway, including its end effector GLI1, can reverse epithelial-to-mesenchymal transition (EMT) which plays an important role in drug resistance of pancreatic cancer cells to Erlotinib (ETB). This study investigated the effect of GLI inhibitors Forskolin (FSK), GANT-61 (GNT), and Arsenic trioxide (ATX) on suppressing the resistance of pancreatic cancer cells to ETB. The effect of GLI inhibitors was evaluated by measuring mRNA expression levels of EMT factors using quantitative RT-PCR. Immunocytochemistry and flow cytometry were used to assess E-cadherin (E-Cad) and GLI1 protein levels. MTT and apoptosis assays were used to evaluate the synergistic effects for the combination treatment of each GLI inhibitor with ETB. Pancreatic cancer cells PANC-1 treated by GNT showed the highest significant reduction in mRNA levels of GLI1 and other EMT pathway genes. Moreover, GNT was able to upregulate E-Cad and downregulate GLI1 proteins, more than FSK, while ATX had no effect. Apoptosis levels of PANC-1 cells following treatment with LD30 concentrations of FSK, GNT, or ATX, showed 57%, 62% and 67%, respectively, in comparison to ETB (∼48%). Importantly, combination treatments of ETB with either FSK, GNT, or ATX demonstrated a significant increase in apoptotic cells reaching 61% (ETB + FSK), 80% (ETB + GNT) or 88% (ETB + ATX). FSK did not have much effect on the drug resistance of PANC-1 cells to ETB. However, GNT, but more effectively ATX, were able to reduce the drug resistance of this cell line to ETB.

Synthesis of gold nanoparticles from leaf Panax notoginseng and its anticancer activity in pancreatic cancer PANC-1 cell lines

Development of novel methods is needed for the synthesis of nanoparticles. Attention on such particles has elevated disquiet about the eco-friendly manner of their fabrication methods. In the present study, we equipped and synthesized gold nanoparticles (AuNPs) from Panax notoginseng; investigated as an environmentally friendly and non-toxic substrate. Amalgamation of AuNPs was distinguished by numerous studies such as UV-absorbance and it shows peak values in the range of 520–550 nm. Nanoparticles sizes are confirmed by dynamic light scattering analysis and it shows 100 nm. Moreover, transmission electron microscopy (TEM) and energy dispersive X-ray analysis (EDX) confirmed the shape of the Au particles present in the synthesized materials. FTIR analysis studies showed the active molecules positioned in the plane of the synthesized particles. The anticancer potential of AuNPs was evaluated in PANC-1 cells. Additionally, AuNPs efficiently induced cytotoxicity, ROS and apoptosis by intonating intrinsic apoptotic gene expressions in PANC-1 cells. Finally, our study confirmed the synthesis of AuNPs from Panax notoginseng, which showed anticancer effects in an environmentally friendly manner.

Pimavanserin tartrate: A potential drug for pancreatic cancer therapy in future

Despite major advances in cancer treatment, pancreatic cancer is still incurable and the treatment outcomes are limited. In the current study, we evaluated the anti‐cancer effects of pimavanserin tartrate (PVT), a drug used for the treatment of Parkinson's disease psychosis. Our observations indicated that, PVT significantly suppressed the proliferation of pancreatic cancer cells by inducing apoptosis without exerting any cytotoxic effects in normal human pancreatic ductal epithelial (HPDE‐6) cells. The colony forming ability of pancreatic cancer cells was significantly inhibited with PVT treatment. Anti‐proliferative and apoptosis inducing effects of PVT were mediated by the inhibition of pAkt (Ser473), Akt, Gli1, Oct‐4, SOX‐2, NANOG and c‐Myc. Akt and Oct‐4 inhibition by PVT treatment was further validated by immunofluorescence analysis. Apoptotic effects of PVT was confirmed by increase in cleavage of caspase‐3 and PARP. Moreover, PVT inhibited the formation of tumorspheres in PANC1 pancreatic cancer cells. Pharmacologically inhibiting or genetically knocking out Akt or Gli1 enhanced the growth suppressive effects of PVT in pancreatic cancer cells. Subsequently, we evaluated the effects of PVT in gemcitabine‐resistant cells. Our results demonstrated that, PVT reduced the survival of MIAPaCa2 gemcitabine‐resistant cells in a concentration and time‐dependent manner. Further mechanistic analysis indicated that, PVT suppressed the phosphorylation of Akt at Ser 473 and inhibited the expression of Gli1, Oct‐4 and c‐Myc in MIAPaCa2 gemcitabine‐resistant cells. Moreover, PVT increased the cleavage of caspase‐3 and PARP as an indicator of apoptosis. Oral administration of PVT suppressed BxPC3 tumor xenografts by 50% in athymic nude mice. In another in vivo experiment, PVT treatment inhibited the growth of orthotopically implanted PANC1 tumors by 75%. Chronic administration of PVT did not exhibit any general signs of toxicity or behavioral side effects in mice. Taken together, our results indicate that pancreatic tumor growth suppression by PVT is orchestrated by inhibition of Akt/Gli1 signaling. Since PVT is already available in the clinic with an established safety profile, our results will accelerate its clinical development for the treatment of patients with pancreatic cancer.Support or Funding InformationSupported in part by R01 grant CA129038, awarded to (S.K.S.) by the National Cancer Institute, Syngenta fellowship grant awarded by Syngenta pharmaceuticals.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Bisdemethoxycurcumin potentiates gemcitabine to induce mitochondrial dysfunctions and apoptosis in human pancreatic adenocarcinoma cells

Pancreatic cancer is a highly aggressive malignancy, gemcitabine is indicated as a standard single agent for the treatment of pancreatic cancer, however it only extends survival by a mere 3–6 weeks. In this present study we investigate whether bisdemethoxycurcumin (BDMC), a derivative of curcumin, potentiates gemcitabine in human pancreatic cancer cells. The result suggested that BDMC produced a synergistic effects with gemcitabine by inducing mitochondrial dysfunctions and apoptosis in PANC‐1 and MiaPaCa‐2 pancreatic cancer cells. By using 2D‐MS, we found 13 essential proteins were significantly changed in response to gemcitabine alone or combined with BDMC. Pharmacological network analysis revealed that glucose‐regulated protein 78 (GRP78) as the hub activated by BDMC. We then demonstrated that BDMC upregulates GRP78 and facilitated apoptosis through eIF2α/CHOP pathway. In addition, DJ‐1 and prohibitin, two identified markers of chemoresistance, were increased by gemcitabine in PANC‐1 cells. This could be reversed by BDMC, suggesting that BDMC partially offsets the chemoresistance induced by gemcitabine. In conclusion, our study shows that BDMC promotes apoptosis through a GRP78‐dependent pathway and mitochondrial dysfunctions, and potentiates the antitumor effect of gemcitabine in human pancreatic cancer cells.Support or Funding InformationThis work was supported by the National Natural Science Foundation of China (No. 81874318, 81673453, 81473235).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Lycopene Inhibits Reactive Oxygen Species-Mediated NF-κB Signaling and Induces Apoptosis in Pancreatic Cancer Cells.

Generation of excess quantities of reactive oxygen species (ROS) caused by mitochondrial dysfunction facilitates rapid growth of pancreatic cancer cells. Elevated ROS levels in cancer cells cause an anti-apoptotic effect by activating survival signaling pathways, such as NF-κB and its target gene expression. Lycopene, a carotenoid found in tomatoes and a potent antioxidant, displays a protective effect against pancreatic cancer. The present study was designed to determine if lycopene induces apoptosis of pancreatic cancer PANC-1 cells by decreasing intracellular and mitochondrial ROS levels, and consequently suppressing NF-κB activation and expression of NF-κB target genes including cIAP1, cIAP2, and survivin. The results show that the lycopene decreased intracellular and mitochondrial ROS levels, mitochondrial function (determined by the mitochondrial membrane potential and oxygen consumption rate), NF-κB activity, and expression of NF-κB-dependent survival genes in PANC-1 cells. Lycopene reduced cell viability with increases in active caspase-3 and the Bax to Bcl-2 ratio in PANC-1 cells. These findings suggest that supplementation of lycopene could potentially reduce the incidence of pancreatic cancer.

Dasatinib can enhance paclitaxel and gemcitabine inhibitory activity in human pancreatic cancer cells

ABSTRACT SRC and its activated form, phospho-SRC (pSRC), are aberrantly activated in pancreatic cancer and SRC represents a potential target for pancreatic cancer therapy. In this paper, we examined the inhibitory effect of dasatinib, a potent SRC inhibitor in combination with paclitaxel or gemcitabine on human and murine pancreatic cancer cell lines. The results showed that p-SRC can be highly expressed in most human and mouse pancreatic cancer cell lines compared with normal human cell lines and can be induced by paclitaxel or gemcitabine in HPAC cells. Dasatinib can enhance the efficacy of paclitaxel or gemcitabine by reducing the cell viability and inhibiting the cell proliferation. Dasatinib with paclitaxel combination exhibits statistically greater inhibition of the cell migration ability than single agent alone, paclitaxel with gemcitabine or FOLFIRINOX (combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin) in HAPC, PANC-1, and BXPC-3 human pancreatic cancer cell lines as well as 8–285 APR and 8–365 APR mouse pancreatic cancer cell lines. In addition, dasatinib with gemcitabine combination also showed statistically greater inhibition of cell migration than single agent alone, paclitaxel with gemcitabine, or FOLFIRINOX in HAPC, PANC-1 and 8–285 APR cells. The combination of dasatinib with paclitaxel or gemcitabine also showed greater inhibition of the colony formation ability of pancreatic cancer cells compared with single-agent monotherapy or FOLFIRINOX. Dasatinib with paclitaxel or gemcitabine combination also inhibits p-SRC, p-STAT3, p-AKT, and/or p-ERK in these pancreatic cancer cells. Therefore, our results support that combined dasatinib and paclitaxel or gemcitabine therapy may be a viable therapeutic approach for human pancreatic cancer.

Knockdown of ISOC1 suppresses cell proliferation in pancreatic cancer in vitro.

Pancreatic cancer is a deadly disease that is frequently associated with mortality at the time of diagnosis due to rapid metastasis, which makes it unsuitable for operative surgery, and resistant to chemotherapy and radiation therapy. Isochorismatase domain-containing protein 1 (ISOC1) has putative isochorismatase activity, and is positively regulated by estrogen in human breast cancer. However, its role in pancreatic cancer has yet to be fully elucidated. Analysis from datasets downloaded from The Cancer Genome Atlas and Genotype-Tissue Expression databases indicated that the ISOC1 mRNA expression level was increased in pancreatic cancer tissues, compared with normal pancreatic tissues. In the present study, it was determined that the human pancreatic cancer cell lines SW 1990, PANC-1 and AsPC-1 had increased expression levels of ISOC1 mRNA, compared with human pancreatic ductal epithelial cells. Additionally, two of the pancreatic cancer cell lines, SW 1990 and PANC-1, transfected with lentivirus-delivered short hairpin RNA, to knockdown the expression of ISOC1, were established. Cell counting and MTT assays indicated that knockdown of ISOC1 decreased the ability of cell growth and proliferation in pancreatic cancer cells. Furthermore, Annexin V staining and caspase-3/7 activity assays demonstrated that inhibition of ISOC1 promoted cell apoptosis via elevation of the expression of caspase-3/7. Furthermore, inhibition of ISOC1 impaired the cell migration and invasive capability of the cells. In conclusion, ISOC1 exerts a role in pancreatic cancer cell growth and apoptosis, and may have a role in pancreatic cancer tumorigenesis.

Inhibition of LINC00994 represses malignant behaviors of pancreatic cancer cells: interacting with miR-765-3p/RUNX2 axis

ABSTRACT Pancreatic cancer exhibits one of the worst prognosis of all human cancers, and it is associated with gene dysregulation. Our microarray results first indicated long intergenic non-protein coding RNA 994 (LINC00994) as an upregulated long non-coding RNA (lncRNA) and miR-765-3p as a downregulated microRNA (miRNA) in pancreatic cancer tissues (Fold change ≥ 2 and P < 0.05; three paired samples). To investigate the role of LINC00994 in pancreatic carcinogenesis, a pair of short hairpin RNA (shRNA) was used to stably knock down the endogenous expression of LINC00994 in Panc-1 and AsPC-1 pancreatic cancer cells in vitro. We found that LINC00994 silencing inhibited the growth, migration and invasion, and promoted the G1 cell cycle arrest and apoptosis in Panc-1 and AsPC-1 cells. Furthermore, the expression of LINC00994 was negatively correlated with that of miR-765-3p in 10 pancreatic cancer specimens. Runt-related transcription factor 2 (RUNX2), a molecule that contributes to the aggressive behaviors of pancreatic cancer, was herein verified as a novel target for miR-765-3p. Like LINC00994, its expression was elevated in pancreatic cancers. Silencing of LINC00994 and RUNX2 reduced each other’s expression in both Panc-1 and AsPC-1 cells. RUNX2 3ʹUTR and LINC00994 competed to bind miR-765-3p. Additionally, LINC00994-silenced cells regained their aggressive behaviors when miR-765-3p was antagonized, which was accompanied with RUNX2 re-expression. Collectively, our study reveals that LINC00994 contributes to the malignant behaviors of pancreatic cancer cells by preventing miR-765-3p from targeting RUNX2. LINC00994 can be considered as a novel therapeutic target against pancreatic cancer.

Antitumor Effects of Glychionide-A Flavonoid in Human Pancreatic Carcinoma Cells Are Mediated by Activation of Apoptotic and Autophagic Pathways, Cell Cycle Arrest, and Disruption of Mitochondrial Membrane Potential.

BackgroundPancreatic cancer has high incidence and low survival rates around the globe, mainly due to late diagnosis and unavailability of efficient chemotherapeutic agents. In the present study, the anticancer potential of glychionide-A was examined against PANC-1 pancreatic cancer cells.Material/MethodsCellTiter-Glo Luminescent Cell Viability Assay Kits were used for assessment of cell viability. Electron microscopy and DAPI staining were used for the detection of apoptosis and autophagy, respectively. Annexin V/PI staining was used for determination of apoptotic cell percentage. Cell cycle distribution and ROS and MMP levels were determined by flow cytometry. Protein expression was examined by Western blot analysis.ResultsThe results revealed that glychionide-A significantly inhibited the proliferation of the PANC-1 pancreatic cancer cells (IC50, 14 μM). However, minimal toxicity was observed against the normal hTRET-HPNE pancreatic cells (IC50 100 μM). The anticancer activity of glychionide-A against the PANC-1 cells was found to be due to induction of autophagy and apoptosis. Glychionide-A prompted apoptosis and autophagy and was also associated with alteration in apoptosis- (Bax, Caspase 9 and Bcl-2) and autophagy- (LC3I, II, Beclin 1 and p62) related protein expression. Glychionide-A also caused the arrest of PANC-1 cells in the G2/M phase of the cell cycle. The percentage of PANC-1 cells in G2 phase increased from 19.5% to 49.4% upon treatment with glychionide-A. Finally, glychionide-A caused an increase in the level of ROS and decline in MMP levels of the PANC-1 pancreatic cancer cells.ConclusionsIn brief, these results reveal that glychionide-A significantly inhibits the growth of pancreatic cancer cells via inducing apoptosis and autophagy, and could prove valuable in the chemotherapeutic treatment of pancreatic cancer. Therefore, further research is needed, especially more advanced in vivo experiments.

ProNGF siRNA inhibits cell proliferation and invasion of pancreatic cancer cells and promotes anoikis

BackgroundPrecursor of nerve growth factor (proNGF) was previously considered biologically inactive; however, it has recently been identified as having important roles in the pathology of cancer development. AimThis study aimed to explore the therapeutic effects of proNGF siRNA on the proliferation, invasion, and anoikis of pancreatic cancer cells and determine the functions of proNGF. MethodsPancreatic ductal adenocarcinoma (PDAC) and paired paracancerous tissue samples were collected from 60 patients for evaluation of proNGF expression by immunohistochemistry staining, qPCR, and western blotting. PDAC cell proliferation, migration, apoptosis, and anoikis following proNGF siRNA knockdown were investigated in two pancreatic cancer cell lines, Panc-1 and Bxpc-3, using BrdU incorporation assays, EdU staining, Ki-67 immunofluorescence (IF) staining, wound-healing assays, transwell invasion assays, and EthD-1 IF staining. Autophagy-related proteins were also measured by western blotting. ResultsLevels of proNGF protein were higher in pancreatic cancer tissues and cells lines than those in paracancerous tissues and normal pancreatic duct epithelial cells, respectively. In vitro, ProNGF knockdown by siRNA led to significantly reduced cell proliferation, remarkably inhibited wound-healing, and reduced the number of invaded PDAC cells in migration and transwell assays. Treatment with proNGF siRNA also downregulated ATG5 and Beclin 1 protein levels, increased those of P62, and increased EthD-1 staining in PDAC cells. ConclusionProNGF expression is elevated in PDAC tissues and cell lines, and proNGF siRNA can inhibit cell proliferation, migration, and invasion, and promote anoikis of pancreatic cancer cells, in which decreased proNGF may participate.

Erratum to Algerian Propolis Potentiates Doxorubicin Mediated Anticancer Effect Against Human Pancreatic PANC-1 Cancer Cell Line through Cell Cycle Arrest, Apoptosis Induction and P-Glycoprotein Inhibition.

Due to an oversight one of the author's name was published wrong in the article entitled "Algerian Propolis Potentiates Doxorubicin Mediated Anticancer Effect Against Human Pancreatic PANC-1 Cancer Cell Line through Cell Cycle Arrest, Apoptosis Induction and P-Glycoprotein Inhibition" in "Anti-Cancer Agents in Medicinal Chemistry, 2018, Vol. 18, No. 3, pp. 375." The correct names of all authors are given below: Rouibah H, Kebsa W, Lahouel M, Zihlif M, Ahram M, Aburmeleih B, Mustafa E, El-Ameer HJ.

β-Pentagalloyl-Glucose Sabotages Pancreatic Cancer Cells and Ameliorates Cachexia in Tumor-Bearing Mice.

Pancreatic cancer cells overexpress the insulin receptor (IR) and the insulin-like growth factor-1 receptor (IGF1R). Activating these receptors, insulin and insulin-like growth factor-1 increase the growth and glycolysis of pancreatic cancer cells. The high glycolysis in pancreatic cancer cells increases whole-body energy expenditure and is therefore involved in the pathogenesis of cancer cachexia. The antagonism of IR and IGF1R may sabotage pancreatic cancer cells and attenuate cancer cachexia. Previous studies have shown that the intracellular regulating system of IR/IGF1R may be functionally interrelated to another intracellular system whose master regulator is hypoxia-inducible factor-1 (HIF-1). In this study, we investigated how the IR/IGF1R and HIF-1 systems are interrelated in pancreatic cancer cells. We also investigated whether a phytochemical, penta-O-galloyl- -D-glucose ( -PGG), antagonizes IR/IGF1R, sabotages pancreatic cancer cells and alleviates cancer cachexia. We found in MiaPaCa2 pancreatic cancer cells that IR/IGF1R activation increased both the -subunit of HIF-1 and caveolin-1. This result suggests that IR/IGF1R, HIF-1 , and caveolin-1 may constitute a feed-forward loop to mediate the effect of IR/IGF1R activation. -PGG inhibited IR/IGF1R activity and decreased glycolytic enzymes in MiaPaCa2 and Panc-1 pancreatic cancer cells. When MiaPaCa2 cells were transplanted in athymic mice, their growth was inhibited by -PGG or by a HIF-1 inhibitor, rhein. -PGG and rhein also decreased glycolytic enzymes in the tumor grafts and reduced liver gluconeogenesis, skeletal-muscle proteolysis and fat lipolysis in the tumor carriers. Cancer-induced body-weight loss, however, was prevented by -PGG but not rhein. In conclusion, -PGG combats pancreatic cancer cells and cures cancer cachexia.

Liraglutide suppresses the metastasis of PANC-1 co-cultured with pancreatic stellate cells through modulating intracellular calcium content.

In this study, we aim to explore the anti-tumor effect of liraglutide (Lira), an anti-diabetic medicine, on pancreatic cancer cell PANC-1 co-cultured with or without pancreatic stellate cells (PSCs). The chemical count kit-8 and Annexin V-FITC apoptosis detection were conducted to investigate the effect of Lira on cell viability and proliferation of PANC-1 with or without PSCs co-culture. Then, the wound healing and transwell experiments were performed to explore the influence of Lira on PANC-1 cells' migration and invasion capabilities. To identify the potential action mechanism of Lira on PANC-1, the expression of E-cadherin and N-cadherin and the intracellular calcium content in PANC-1, after Lira administration, were detected. The results indicated that Lira in 100 and 1,000 nmol/L, effectively decreased the cell viability and dose-dependently promoted cell apoptosis of PANC-1 co-cultured with or without PSCs. Lira significantly reduced the migration and invasion of PANC-1 and also reduced the inducing effect of PSCs to PANC-1. Lira effectively induced the expression of E-cadherin and suppressed the expression of N-cadherin with a dose-dependent manner. Otherwise, Lira significantly reduced the abnormal high content of calcium in PANC-1 and also weakened the elevation of calcium in PANC-1 induced by cell-cell interaction. The current study firstly indicated that Lira suppressed the cell proliferation, migration and invasion of PANC-1 with or without PSCs co-culture. This effect was partially due to the calcium modulation of Lira and its influence on Ca2+-binding proteins, such as E-cadherin and N-cadherin.

Structure-guided design of anti-cancer ribonucleotide reductase inhibitors

Ribonucleotide reductase (RR) catalyses the rate-limiting step of dNTP synthesis, establishing it as an important cancer target. While RR is traditionally inhibited by nucleoside-based antimetabolites, we recently discovered a naphthyl salicyl acyl hydrazone-based inhibitor (NSAH) that binds reversibly to the catalytic site (C-site). Here we report the synthesis and in vitro evaluation of 13 distinct compounds (TP1-13) with improved binding to hRR over NSAH (TP8), with lower KD’s and more predicted residue interactions. Moreover, TP6 displayed the greatest growth inhibiting effect in the Panc1 pancreatic cancer cell line with an IC50 of 0.393 µM. This represents more than a 2-fold improvement over NSAH, making TP6 the most potent compound against pancreatic cancer emerging from the hydrazone inhibitors. NSAH was optimised by the addition of cyclic and polar groups replacing the naphthyl moiety, which occupies the phosphate-binding pocket in the C-site, establishing a new direction in inhibitor design.

RETRACTED: Long non-coding RNA HULC promotes proliferation, migration and invasion of pancreatic cancer cells by down-regulating microRNA-15a

Pancreatic cancer is a common and lethal cancer in digestive system. This study investigated the potential oncogenic effects of lncRNA HULC on pancreatic cancer. Briefly, qRT-PCR was conducted to measure the expression of HULC and miR-15a in pancreatic tissues and cells. Cell transfection was used to change the expression of HULC and miR-15a in pancreatic cancer Panc-1 cells. The viability, migration and invasion and apoptosis of Panc-1 cells after relevant transfection were detected using CCK-8 assay, two chamber transwell assay and Guava Nexin assay, respectively. Results found that HULC had a higher expression level, while miR-15a had a lower expression level in pancreatic cancer tissues. Overexpression of HULC promoted the proliferation, migration and invasion of Panc-1 cells. Suppression of HULC had opposite effects and dramatically induced cell apoptosis. Moreover, HULC negatively regulated the expression of miR-15a in Panc-1 cells. miR-15a participated in the effects of HULC on Panc-1 cells. Furthermore, overexpression of HULC activated PI3K/AKT pathway in Panc-1 cells by down-regulating miR-15a. In conclusion, HULC exerted oncogenic role in pancreatic cancer. Overexpression of HULC promoted the proliferation, migration and invasion of pancreatic cancer cells by down-regulating miR-15a and then activating PI3K/AKT pathway.