Pancreatic Carcinoma Cells Research Articles

Oridonin induces autophagy-mediated cell death in pancreatic cancer by activating the c-Jun N-terminal kinase pathway and inhibiting phosphoinositide 3-kinase signaling.

BackgroundOridonin is a diterpenoid isolated from Rabdosia rubescens that has potent anticancer activity. This study set out to investigate the antitumor effects of oridonin in pancreatic carcinoma (PC) and their underlying mechanisms.MethodsTo investigate the antitumor effects of oridonin, we developed an orthotopic C57BL/6 mouse model of PC. After successful establishment of the model, the mice were given a daily intraperitoneal injection of phosphate-buffered saline containing 0.1% dimethyl sulfoxide or oridonin for 2 weeks. In vitro experiments including MTT assay and flow cytometry were performed to examine cell viability and apoptosis. Panc-1 and Panc02 cells were transfected with a green fluorescent protein (GFP)-LC3 plasmid. After the cells had been treated with or without 20 μM oridonin and 10 μM 3-MA, the formation of GFP-LC3 puncta was detected by fluorescence microscopy. The levels of the autophagy-related proteins Beclin-1, LC3, and p62 were measured by western blotting.ResultsOridonin inhibited the proliferation of PC cells and induced their apoptosis in vitro and in vivo. Treatment with oridonin also led to an increase in the quantity of LC3B II protein and upregulation of the p62 and Beclin-1 levels in PC cells. The effects of oridonin on PC cell proliferation, apoptosis, and autophagy were mediated via the simultaneous inhibition of the phosphoinositide 3-kinase pathway and activation of the c-Jun N-terminal kinase pathway.ConclusionsOur study is the first to confirm the antitumor and autophagy-activating effects of oridonin on PC cells. In light of these results, oridonin may be a promising therapeutic agent for PC.

WDR5-H3K4me3 epigenetic axis regulates OPN expression to compensate PD-L1 function to promote pancreatic cancer immune escape

BackgroundDespite PD-L1 (Programmed death receptor ligand-1) expression on tumor cells and cytotoxic T lymphocytes tumor infiltration in the tumor microenvironment, human pancreatic cancer stands out as one of the human...

A multi-cellular molecular signaling and functional network map of C-C motif chemokine ligand 18 (CCL18): a chemokine with immunosuppressive and pro-tumor functions.

The C-C Motif Chemokine Ligand 18 (CCL18) is a beta-chemokine sub-family member with immunomodulatory functions in primates. CCL18-dependent migration and epithelial-to-mesenchymal transition of oral squamous cell carcinoma, squamous cell carcinoma of head and neck, breast cancer, hepatocellular carcinoma, non-small cell lung carcinoma, ovarian cancer, pancreatic ductal carcinoma and bladder cancer cells are well-established. In the tumor niche, tumor-associated macrophages produce CCL18 and its overexpression is correlated with reduced patient survival in multiple cancers. Although multiple receptors including C-C chemokine receptor type 3 (CCR3), type 6 (CCR6), type 8 (CCR8) and G-protein coupled estrogen receptor (GPER1) are reported for CCL18, thePhosphatidylinositol Transfer Protein, Membrane-Associated 3 (PITPNM3) receptor is currently considered as its predominant receptor. Characterization of the molecular events and check points associated with the immunosuppressive and cancer progression support functions induced by CCL18 for their potential towards therapeutic applications is an area of active research. Hence, in this study, we assembled 917 signaling events reported to be induced by CCL18 through their studied receptors in diverse cell types as an integrated knowledgebase for reference, data integration and gene-set enrichment analysis of global transcriptomic and/or proteomics datasets.

Study of the Mechanism by Which Curcumin Cooperates with Sestrin2 to Inhibit the Growth of Pancreatic Cancer.

Background Pancreatic carcinoma is a malignant tumor with a high fatality rate, and the increased resistance of pancreatic carcinoma to chemotherapy has become a difficult problem in clinical practice. Hence, it is imperative to develop an effective treatment for pancreatic cancer. Sestrins are a class of stress-induced proteins that have antioxidation functions, regulating cell growth and metabolism. Curcumin is a natural pigment isolated from turmeric. Several studies have also suggested that this molecule has multiple pharmacological effects, such as anti-inflammatory, antioxidant, and antitumor effects. However, there are insufficient studies on curcumin cooperating with the sestrin family to inhibit tumors, and the mechanism is still unclear. Our aim was to observe the potential anticancer effects of curcumin combined with the sestrin family on pancreatic carcinoma and probe its possible molecular mechanisms. Methods Lentiviral infection, real-time fluorescence quantitative PCR assays, Cell Counting Kit-8 assays, real-time cell analysis technology, colony formation assays, wound healing assays, Transwell invasion assays, protein extraction, and western blots (WBs) were used to evaluate the effect of curcumin combined with sestrin2 on the proliferation, invasion, and migration of pancreatic carcinoma cells. Results The results revealed that curcumin cooperated with sestrin2 to significantly suppress pancreatic cancer. In addition, we determined that sestrin2 cooperated with curcumin to inhibit pancreatic cancer by specifically targeting Nrf2/Keap1/HO-1/NQO-1. Conclusion These findings clarify that curcumin-mediated synergistic targeting of sestrin2 is a potentially valuable treatment for pancreatic cancer.

LncRNA HCG11/miR-579-3p/MDM2 axis modulates malignant biological properties in pancreatic carcinoma via Notch/Hes1 signaling pathway.

Background: Increasing reports have revealed that dysregulated expression of long non-coding RNAs (lncRNAs) is involved in pancreatic carcinoma progression. This study intends to explore the function and molecular mechanism of lncRNA HLA complex group 11 (HCG11) in pancreatic carcinoma.Methods: The expression profiles of HCG11 in pancreatic carcinoma samples were detected by qPCR. Bioinformatics analysis was applied to detect the associations among HCG11/miR-579-3p/MDM2. The malignant properties of pancreatic carcinoma cells were measured by numerous biological assays. Xenograft model was exploited to detect the effect of HCG11 on tumor growth.Results: A significant increase of HCG11 was occurred in pancreatic carcinoma samples. Knockdown of HCG11 suppressed the progression of pancreatic carcinoma cells. Bioinformatics analysis revealed that HCG11 upregulated MDM2 expression by competitively targeting miR-579-3p. The rescue assays showed that miR-579-3p reversed cell behaviors caused by HCG11, and MDM2 reversed cell properties induced by miR-579-3p. The Notch1 intracellular domain (NICD) and Hes1 protein levels were increased by overexpression of HCG11/MDM2. The tumor growth was suppressed after depletion of HCG11, followed by suppressing Ki67, PCNA and Vimentin expression, increasing TUNEL-positive cells and E-cadherin expression.Conclusions: Our observations highlighted that HCG11 contributed to the progression of pancreatic carcinoma by promoting growth and aggressiveness, and inhibiting apoptosis via miR-579-3p/MDM2/Notch/Hes1 axis.

Cancer Cells Shuttle Extracellular Vesicles Containing Oncogenic Mutant p53 Proteins to the Tumor Microenvironment

Simple SummaryIn addition to the classical cell-to-cell communication patterns, extracellular vesicles (EVs) are instrumental in conveying molecular messages across cell types and have the potential to mediate changes at a tissue level. Since it is now appreciated that carcinomas are fundamentally reliant on two-way communication with activated cells in the tumor microenvironment, elucidating the roles of EVs exchange and of the cargo that is transferred is essential to obtain a thorough understanding of tumor progression. This study reveals that mutant p53 proteins—the result of the most frequent mutated gene in human cancer—are packed into EVs and delivered to neighboring cells with the potential to reprogram immune cells and subsequently establish a positive feedback loop that will enhance tumor progression. This non-cell autonomous role of mutant p53 is evidence of an extra layer of communication that is orchestrated by smaller vesicles that transfer oncogenic elements between cellular entities. Building on the foundation of our work on mutant p53, future studies may aim to characterize the potential activation of additional oncogenes, thus opening new paths of research at the interface of extracellular vesicles, cancer, and evolution.Extracellular vesicles (EVs) shed by cancer cells play a major role in mediating the transfer of molecular information by reprogramming the tumor microenvironment (TME). TP53 (encoding the p53 protein) is the most mutated gene across many cancer types. Mutations in TP53 not only result in the loss of its tumor-suppressive properties but also results in the acquisition of novel gain-of-functions (GOF) that promote the growth of cancer cells. Here, we demonstrate that GOF mutant p53 proteins can be transferred via EVs to neighboring cancer cells and to macrophages, thus modulating them to release tumor supportive cytokines. Our data from pancreatic, lung, and colon carcinoma cell lines demonstrate that the mutant p53 protein can be selectively sorted into EVs. More specifically, mutant p53 proteins in EVs can be taken up by neighboring cells and mutant p53 expression is found in non-tumor cells in both human cancers and in non-human tissues in human xenografts. Our findings shed light on the intricate methods in which specific GOF p53 mutants can promote oncogenic mechanisms by reprogramming and then recruiting non-cancerous elements for tumor progression.

Metabolic Response of Pancreatic Carcinoma Cells under Treatment with Dichloroacetate.

In modern oncology, the analysis and evaluation of treatment response are still challenging. Hence, we used a 13C-guided approach to study the impacts of the small molecule dichloroacetate (DCA) upon the metabolic response of pancreatic cancer cells. Two different oncogenic PI3K-driven pancreatic cancer cell lines, 9580 and 10,158, respectively, were treated with 75 mM DCA for 18 h. In the presence of [U-13C6]glucose, the effects of DCA treatment in the core carbon metabolism were analyzed in these cells using gas chromatography–mass spectrometry (GC/MS). 13C-enrichments and isotopologue profiles of key amino acids revealed considerable effects of the DCA treatment upon glucose metabolism. The DCA treatment of the two pancreatic cell lines resulted in a significantly decreased incorporation of [U-13C6]glucose into the amino acids alanine, aspartate, glutamate, glycine, proline and serine in treated, but not in untreated, cancer cells. For both cell lines, the data indicated some activation of pyruvate dehydrogenase with increased carbon flux via the TCA cycle, but also massive inhibition of glycolytic flux and amino acid biosynthesis presumably by inhibition of the PI3K/Akt/mTORC axis. Together, it appears worthwhile to study the early treatment response in DCA-guided or accompanied cancer therapy in more detail, since it could open new avenues for improved diagnosis and therapeutic protocols of cancer.

Chlorophenyl-benzoxime inhibits pancreatic cancer cell proliferation, invasion and migration by down-regulating the expressions of interleukin-8 and cyclooxygenase-2

Purpose: To investigate the effects of chlorophenyl-benzoxime (CPBZX) on pancreatic cancer (PC) cell proliferation, invasion and migration, and the underlying mechanism of action.
 Methods: Pancreatic carcinoma cell lines (HuP-T4, HuP-T3 and BxPC-3) were cultured in Dulbecco's Modified Eagle medium (DMEM) containing 10 % fetal bovine serum (FBS), penicillin (100 U/mL) and streptomycin (10 μg/mL) at 37 ˚C in a humidified atmosphere containing 5 % CO2 and 95 % air. Cell proliferation was assessed using MTT assay. Real-time quantitative polymerase chain reaction (qRTPCR) and Western blotting were employed for the determination of changes in the levels of expression of carcinoembryonic antigen (CEA), interleukin-8 (IL-8) and cyclooxygenase-2 (COX 2). Cell invasion and migration were determined using Transwell and wound healing assays, respectively.
 Results: The results of MTT assay showed that CPBZX significantly and dose-dependently inhibited the proliferation of PC cells (p < 0.05). Incubation of HuP-T4 cells with CPBZX significantly and dosedependently reduced the invasive ability of the cells (p < 0.05). The migratory ability of HuP-T4 cells was also significantly and dose-dependently inhibited by CPBZX (p < 0.05). The results of Western blotting and qRT PCR showed that CPBZX treatment significantly and dose-dependently upregulated CEA mRNA expression (p < 0.05). On the other hand, the expressions of IL-8 and COX-2 were significantly and dose-dependently down-regulated by CPBZX. Treatment of pancreatic tumor mice with CPBZX significantly decreased tumor growth and metastasis of tumor cells to the pulmonary tissues, liver and lymph nodes (p < 0.05).
 Conclusion: The results of this study suggest that CPBZX inhibits the development and metastasis of PC via the down-regulation of IL-8 and COX 2 expressions, and therefore may find application in pancreatic cancer therapy.

Cryptic Biosynthesis of the Berkeleypenostatins from Coculture of Extremophilic Penicillium sp.

Coculture fermentation of Penicillium fuscum and P. camembertii/clavigerum yielded berkeleypenostatins A-G (1-7) as well as the previously reported berkeleylactones A-H, the known macrolide A26771B, citrinin, and patulin. As was true with the berkeleylactones, there was no evidence of the berkeleypenostatins in either axenic culture. The structures were deduced from analyses of spectral data, and the absolute configuration of berkeleypenostatin A (1) was determined by single-crystal X-ray crystallography. Berkeleypenostatins A (1) and E (5) inhibited migration of human pancreatic carcinoma cells (HPAF-II). Both compounds were tested by the NCI Developmental Therapeutics Program. In the NCI 60 cell five-dose screen, berkeleypenostatin E (5) was the more active of the two, with 1-10 μM total growth inhibition (TGI) of all leukemia cell lines, as well as the majority of colon, CNS, melanoma, ovarian, prostate, renal, and breast cancer cell lines.

Heparanase 2 (Hpa2) attenuates the growth of pancreatic carcinoma

While the pro-tumorigenic properties of the ECM-degrading heparanase enzyme are well documented, the role of its close homolog, heparanase 2 (Hpa2), in cancer is largely unknown. We examined the role of Hpa2 in pancreatic cancer, a malignancy characterized by a dense fibrotic ECM associated with poor response to treatment and bad prognosis. We show that pancreatic ductal adenocarcinoma (PDAC) patients that exhibit high levels of Hpa2 survive longer than patients with low levels of Hpa2. Strikingly, overexpression of Hpa2 in pancreatic carcinoma cells resulted in a most prominent decrease in the growth of tumors implanted orthotopically and intraperitoneally, whereas Hpa2 silencing resulted in bigger tumors. We further found that Hpa2 enhances endoplasmic reticulum (ER) stress response and renders cells more sensitive to external stress, associating with increased apoptosis. Interestingly, we observed that ER stress induces the expression of Hpa2, thus establishing a feedback loop by which Hpa2 enhances ER stress that, in turn, induces Hpa2 expression. This leads to increased apoptosis and attenuated tumor growth. Altogether, Hpa2 emerges as a powerful tumor suppressor in pancreatic cancer.

Retracted: Antiproliferative Effects of Matricine in Gemcitabine-Resistant Human Pancreatic Carcinoma Cells Are Mediated via Mitochondrial-Mediated Apoptosis, Inhibition of Cell Migration, Invasion Suppression, and Mammalian Target of Rapamycin (mTOR)-TOR/PI3K/AKT Signalling Pathway.

An editorial decision has been made to retract this manuscript due to breach of publishing guidelines, following the identification of non-original and manipulated figures. Reference: Kaifeng Fang, Li Wang, LuJia Chen, Tao Liu, Zhi Fang: Antiproliferative Effects of Matricine in Gemcitabine-Resistant Human Pancreatic Carcinoma Cells Are Mediated via Mitochondrial-Mediated Apoptosis, Inhibition of Cell Migration, Invasion Suppression, and Mammalian Target of Rapamycin (mTOR)-TOR/PI3K/AKT Signalling Pathway. Med Sci Monit 2019; 25:2943-2949.10.12659/MSM.914244.

Isoalantolactone inhibits pancreatic cancer proliferation by regulation of PI3K and Wnt signal pathway.

Background/aimsIsoalantolactone (IATL) is one of multiple isomeric sesquiterpene lactones and is isolated from inula helenium. IATL has multiple functions such as antibacterial, antihelminthic and antiproliferative activities. IATL also inhibits pancreatic cancer proliferation and induces apoptosis by increasing ROS production. However, the detailed mechanism of IATL-mediated pancreatic cancer apoptosis remains largely unknown.MethodsIn current study, pancreatic carcinoma cell lines (PANC-1, AsPC-1, BxPC-3) and a mouse xenograft model were used to determine the mechanism of IATL-mediated toxic effects.ResultsIATL (20μM) inhibited pancreatic adenocarcinoma cell lines proliferation in a time-dependent way; while scratch assay showed that IATL significantly inhibited PANC-1 scratch closure (P<0.05); Invasion assays indicated that IATL significantly attenuated pancreatic adenocarcinoma cell lines invasion on matrigel. Signal analysis showed that IATL inhibited pancreatic adenocarcinoma cell proliferation by blocking EGF-PI3K-Skp2-Akt signal axis. Moreover, IATL induced pancreatic adenocarcinoma cell apoptosis by increasing cytosolic Caspase3 and Box expression. This apoptosis was mediated by inhibition of canonical wnt signal pathway. Finally, xenograft studies showed that IATL also significantly inhibited pancreatic adenocarcinoma cell proliferation and induced pancreatic adenocarcinoma cell apoptosis in vivo.ConclusionsIATL inhibits pancreatic cancer proliferation and induces apoptosis on cellular and in vivo models. Signal pathway studies reveal that EGF-PI3K-Skp2-Akt signal axis and canonical wnt pathway are involved in IATL-mediated cellular proliferation inhibition and apoptosis. These studies indicate that IATL may provide a future potential therapy for pancreatic cancer.

Dihydromyricetin Inhibits Proliferation, Migration, and Invasion of Pancreatic Cancer Cells by Regulating miR-509-3p/PRMT5 Pathway

To explore the role of dihydromyricetin (DHM) in regulating proliferation, metastasis and infiltration of pancreatic cancer cells, we treated the pancreatic adenocarcinoma cell line SW1990 with 10 µmol/L, 20 µmol/L, and 40 µmol/L DHM. Proliferation was determined by the MTT assay. Cell metastasis and infiltration were determined by the Transwell migration assay. The protein expression levels of cyclin D1, p21, MMP-2, MMP-9, and PRMT5 were determined by Western blot. Quantitative PCR was used to determine expression of miR-509-3p and PRMT5 mRNA. The relationship between miR-509-3p and PRMT5 was analyzed by bioinformatic prediction and the dual luciferase reporter assay. SW1990 cells were transfected with miR-509-3p, si-PRMT5 and anti-miR-509-3p (following treatment with 40 µmol/L DHM) to determine their effects on biological behaviors of cells. The inhibition rate of SW1990 cells, p21 protein and miR-509-3p expression were increased by DHM. Moreover, the number of infiltrating and metastatic cells, protein levels of cyclin D1, MMP-2, MMP-9, and PRMT5, and mRNA levels of PRMT5 were decreased by DHM. miR-509-3p regulates expression of its target PRMT5 mRNA. Inhibition rate of SW1990 cell proliferation and protein level p21 were significantly increased by overexpression of miR-509-3p or knockdown of PRMT5 expression, while the number of invasive cells and protein expression levels of cyclin D1, MMP-2 and MMP-9 were remarkably reduced by miR-509-3p overexpression or PRMT5 knockdown. Inhibition of miR-509-3p counteract the inhibitory effects of DHM on SW1990 cell proliferation and metastasis. Therefore, DHM inhibits proliferation and metastasis of pancreatic carcinoma cells by regulating the miR-509-3p/PRMT5 pathway.

Long Noncoding RNA DUXAP8 Promotes Pancreatic Carcinoma Cell Migration and Invasion Via Pathway by miR-448/WTAP/Fak Signaling Axis.

ObjectivesPancreatic carcinoma (PC) has become the fourth leading cause of cancer deaths. Long noncoding RNA DUXAP8 has also been reported to play a regulatory role in PC progression. However, its molecular mechanism in PC is not fully elucidated.MethodsQuantitative real-time polymerase chain reaction was used to detect the levels of DUXAP8, microRNA (miR)-448, Wilms tumor 1–associating protein (WTAP), focal adhesion kinase (Fak), and matrix metallopeptidase 2/9. Western blotting was carried out to detect matrix metallopeptidase 2/9, WTAP, Fak, and p-Fak. The interaction between DUXAP8 and miR-448 as well as WTAP and miR-448 was validated by bioinformatics and dual-luciferase reporter assays. Transwell assay was used to analyze cell invasion and migration. 3-[4,5-Dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay was used to analyze cell proliferation.ResultsDUXAP8 was upregulated, whereas miR-448 was downregulated in PC tissue and cells. Meanwhile, DUXAP8 knockdown or miR-448 overexpression inhibited migration, invasion, and proliferation of PC cells. DUXAP8 directly targeted miR-448, and miR-448 directly bound to WTAP. Downregulation of miR-448 reversed the inhibition of migration and invasion of PC cells by DUXAP8 knockdown.ConclusionsDUXAP8 sponges miR-448 to modulate migration, invasion, and proliferation of PC cells, indicating a novel mechanistic role of DUXAP8 in the regulation of PC progression.

Long non-coding RNA TMPO-AS1 serves as a tumor promoter in pancreatic carcinoma by regulating miR-383-5p/SOX11.

The dysregulation of lncRNA TMPO antisense RNA 1 (TMPO-AS1) has been detected in various malignant tumors. However, the role of lncRNA TMPO-AS1 remains unclear in pancreatic carcinoma. The present study aimed to elucidate the functional mechanism of TMPO-AS1 in pancreatic carcinoma. In the present study, RT-qPCR, western blotting, MTT, Transwell, luciferase reporter and xenograft assays were used to investigate the role of lncRNA TMPO-AS1 in pancreatic carcinoma. Upregulation of lncRNA TMPO-AS1 was revealed in pancreatic carcinoma tissues and cells. Furthermore, knockdown of TMPO-AS1 restrained cell proliferation and motility in pancreatic carcinoma. In addition, microRNA (miR)-383-5p acted as a ‘sponge’ for lncRNA TMPO-AS1. The expression levels of lncRNA TMPO-AS1 and miR-383-5p were mutually inhibited in pancreatic carcinoma. Moreover, miR-383-5p was revealed to directly target SRY-related high-mobility group box 11 (SOX11). Notably, SOX11 could promote the occurrence of pancreatic carcinoma by interacting with the lncRNA TMPO-AS1/miR-383-5p axis. In conclusion, upregulation of lncRNA TMPO-AS1 promoted tumor growth, cell migration and invasion in pancreatic carcinoma by downregulating miR-383-5p and upregulating SOX11.

CLytA-DAAO Chimeric Enzyme Bound to Magnetic Nanoparticles. A New Therapeutical Approach for Cancer Patients?

D-amino acid oxidase (DAAO) is an enzyme that catalyzes the oxidation of D-amino acids generating H2O2. The enzymatic chimera formed by DAAO bound to the choline-binding domain of N-acetylmuramoyl-L-alanine amidase (CLytA) induces cytotoxicity in several pancreatic and colorectal carcinoma and glioblastoma cell models. In the current work, we determined whether the effect of CLytA-DAAO immobilized in magnetic nanoparticles, gold nanoparticles, and alginate capsules offered some advantages as compared to the free CLytA-DAAO. Results indicate that the immobilization of CLytA-DAAO in magnetic nanoparticles increases the stability of the enzyme, extending its time of action. Besides, we compared the effect induced by CLytA-DAAO with the direct addition of hydrogen peroxide, demonstrating that the progressive generation of reactive oxygen species by CLytA-DAAO is more effective in inducing cytotoxicity than the direct addition of H2O2. Furthermore, a pilot study has been initiated in biopsies obtained from pancreatic and colorectal carcinoma and glioblastoma patients to evaluate the expression of the main genes involved in resistance to CLytA-DAAO cytotoxicity. Based on our findings, we propose that CLytA-DAAO immobilized in magnetic nanoparticles could be effective in a high percentage of patients and, therefore, be used as an anti-cancer therapy for pancreatic and colorectal carcinoma and glioblastoma.

PDK4 dictates metabolic resistance to ferroptosis by suppressing pyruvate oxidation and fatty acid synthesis

Although induction of ferroptosis, an iron-dependent form of non-apoptotic cell death, has emerged as an anticancer strategy, the metabolic basis of ferroptotic death remains poorly elucidated. Here, we show that glucose determines the sensitivity of human pancreatic ductal carcinoma cells to ferroptosis induced by pharmacologically inhibiting system xc-. Mechanistically, SLC2A1-mediated glucose uptake promotes glycolysis and, thus, facilitates pyruvate oxidation, fuels the tricyclic acid cycle, and stimulates fatty acid synthesis, which finally facilitates lipid peroxidation-dependent ferroptotic death. Screening of a small interfering RNA (siRNA) library targeting metabolic enzymes leads to identification of pyruvate dehydrogenase kinase 4 (PDK4) as the top gene responsible for ferroptosis resistance. PDK4 inhibits ferroptosis by blocking pyruvate dehydrogenase-dependent pyruvate oxidation. Inhibiting PDK4 enhances the anticancer activity of system xc- inhibitors invitro and in suitable preclinical mouse models (e.g., a high-fat diet diabetes model). These findings reveal metabolic reprogramming as a potential target for overcoming ferroptosis resistance.

MiR24-3p activity after delivery into pancreatic carcinoma cell lines exerts profound tumor-inhibitory effects through distinct pathways of apoptosis and autophagy induction.

Pancreatic cancer is among the most detrimental tumors, with novel treatment options urgently needed. The pathological downregulation of a miRNA in tumors can lead to the overexpression of oncogenes, thus suggesting miRNA replacement as novel strategy in cancer therapy. While the role of miR24 in cancer, including pancreatic carcinoma, has been described as ambiguous, it may hold great promise and deserves further studies. Here, we comprehensively analyze the effects of miR24-3p replacement in a set of pancreatic carcinoma cell lines. Transfection of miR24-3p mimics leads to profound cell inhibition in various 2D and 3D cell assays, based on the induction of apoptosis, autophagy and ROS. Comprehensive analyses of miR24-3p effects on the molecular level reveal the transcriptional regulation of several important oncogenes and oncogenic pathways. Based on these findings, miRNA replacement therapy was preclinically explored by treating tumor xenograft-bearing mice with miR24-3p mimics formulated in polymeric nanoparticles. The obtained tumor inhibition was associated with the induction of apoptosis and necrosis. Taken together, we identify miR24-3p as powerful tumor-inhibitory miRNA for replacement therapy, and describe a complex network of oncogenic pathways affected by miR24.

Dauricine inhibits human pancreatic carcinoma cell proliferation through regulating miRNAs.

Pancreatic cancer is one of the most malignant digestive tract tumors with the worst prognosis. Dauricine (Dau) can inhibit the proliferation of the pancreatic cancer cell line, and has the potential to be used as an adjuvant drug against pancreatic cancer; however, the working mechanism of Dau has not been elucidated. To unravel the effects and mechanisms of Dau on proteins and metabolic pathways, we evaluated the mRNA and microRNA expression in BxPC3 cells treated with Dau. The differences in the gene expression were compared using principal component analysis using mRNA and miRNA data to detect and analyze the sample discrimination. 187 miRNA and 907 mRNA that were significantly differentially expressed were identified using Python programming. On comparing genes and miRNAs in the DISEASES database, 79 known miRNA and 47 mRNA were found to be affected by Dau. The up-regulated and down-regulated genes were annotated with GO biological processes to determine the functional effect. Interactions between mRNA and mRNA were analyzed using the STRING database and the miRBase database was queried to obtain experimentally verified interactions between miRNA and mRNA as edges of miRNA and mRNA in the network. Finally, 413 sites and 2125 sides of the network were obtained, including 1 up-regulated and 18 down-regulated miRNAs. The expression of 19 miRNAs was identified by qPCR. The analysis of the protein-protein interaction network, using the Molecular Complex Detection (MCODE) plug-in of cytoscape, helped in identifying 12 important sub-networks. Most subnets are indirectly or directly related to specific miRNAs. This study provides evidence for the anticancer effect of Dau as a potential anticancer compound.

The clinical significance of microRNA-409 in pancreatic carcinoma and associated tumor cellular functions

ABSTRACT In recent years, the increasing incidence of pancreatic carcinoma (PC) patients has become one of the hot issues in the world. microRNAs (miRNAs) can act as oncogenes or tumor suppressor genes and have unpredictable effects on tumors, thus affecting the prognosis and survival of cancer patients. In this paper, we mainly studied the role of microRNA (miR)-409 in PC. The expression levels of miR-409 were analyzed by qRT-PCR. Kaplan-Meier curve and Cox regression were used to analyze the relationship between miR-409 and patient prognosis. The effects of miR-409 on the abilities of proliferation, migration and invasion were detected by CCK-8 and Transwell. The expression levels of miR-409 were down-regulated in PC, compared with normal controls. The prognosis of patients with low miR-409 expression is significantly poor in comparison with those with high expression. The down-regulation of miR-409 was conducive to the proliferation, migration and invasion of PC cells. miR-409 is a tumor suppressor of PC, the clinical significance of miR-409 in pancreatic cancer and related tumor cell function was clarified.