LncRNA-BLACAT1 Facilitates Proliferation, Migration and Aerobic Glycolysis of Pancreatic Cancer Cells by Repressing CDKN1C via EZH2-Induced H3K27me3

Gemcitabine (GEM) resistance remains a challenging clinical issue to overcome in chemotherapy against pancreatic cancer. We previously demonstrated that miR-210 derived from pancreatic cancer stem cells enhanced the GEM-resistant properties of pancreatic cancer cells, thus identifying miR-210 as an oncogenic miRNA. Herein, we report the existence of an upstream effector that acts as a competing endogenous RNA (ceRNA) to miR-210. Bioinformatic screening was performed to identify lncRNAs with a binding relationship to miR-210. Overexpression and interference vectors were constructed to demonstrate the effect of ceRNA activity in pancreatic cell behavior, both in vitro and in vivo. DLEU2L (deleted in lymphocytic leukemia 2-like), which is expressed at low levels in pancreatic cancer tissues, was shown to exhibit a binding relationship with miR-210-3p. Overexpression of DLEU2L and silencing of miR-210-3p suppressed the proliferation, migration, and invasion of pancreatic cancer cells while promoting apoptosis. These effects occurred via the inhibition of the Warburg effect (aerobic glycolysis) and AKT/mTOR signaling. In addition, we showed that BRCA2 is a target gene of miR-210-3p, and the downregulation of miR-210-3p by DLEU2L effectively induced an upregulation of BRCA2 via the ceRNA mechanism. In vivo, DLEU2L overexpression and miR-210-3p interference suppressed pancreatic tumor progression, consistent with the results of in vitro studies. The findings of our study establish DLEU2L as a ceRNA to miR-210-3p and reveal the critical role of the DLEU2L/miR-210-3p crosstalk in targeting GEM resistance.

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RAD51 is a potential marker for prognosis and regulates cell proliferation in pancreatic cancer

Cancer Cell International ◽

10.1186/s12935-019-1077-6 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 1

Author(s):

Xiaomeng Zhang ◽

Ningyi Ma ◽

Weiqiang Yao ◽

Shuo Li ◽

Zhigang Ren

Keyword(s):

Pancreatic Cancer ◽

Cell Proliferation ◽

Overall Survival ◽

Cancer Cells ◽

Cancer Patients ◽

Aerobic Glycolysis ◽

Cell Counting ◽

Survival Prediction ◽

Pancreatic Cancer Cells ◽

The Impact

Abstract Background The DNA damage and repair pathway is considered a promising target for developing strategies against cancer. RAD51, also known as RECA, is a recombinase that performs the critical step in homologous recombination. RAD51 has recently received considerable attention due to its function in tumor progression and its decisive role in tumor resistance to chemotherapy. However, its role in pancreatic cancer has seldom been investigated. In this report, we provide evidence that RAD51, regulated by KRAS, promotes pancreatic cancer cell proliferation. Furthermore, RAD51 regulated aerobic glycolysis by targeting hypoxia inducible factor 1α (HIF1α). Methods TCGA (The Cancer Genome Atlas) dataset analysis was used to examine the impact of RAD51 expression on overall survival of pancreatic cancer patients. Lentivirus-mediated transduction was used to silence RAD51 and KRAS expression. Quantitative real-time PCR and western blot analysis validated the efficacy of the knockdown effect. Analysis of the glycolysis process in pancreatic cancer cells was also performed. Cell proliferation was determined using a CCK-8 (Cell Counting Kit-8) proliferation assay. Results Pancreatic cancer patients with higher levels of RAD51 exhibited worse survival. In pancreatic cancer cells, RAD51 positively regulated cell proliferation, decreased intracellular reactive oxygen species (ROS) production and increased the HIF1α protein level. KRAS/MEK/ERK activation increased RAD51 expression. In addition, RAD51 was a positive regulator of aerobic glycolysis. Conclusion The present study reveals novel roles for RAD51 in pancreatic cancer that are associated with overall survival prediction, possibly through a mechanism involving regulation of aerobic glycolysis. These findings may provide new predictive and treatment targets for pancreatic cancer.

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AMPK Inhibition Suppresses the Malignant Phenotype of Pancreatic Cancer Cells in Part by Attenuating Aerobic Glycolysis

Journal of Cancer ◽

10.7150/jca.28299 ◽

2019 ◽

Vol 10 (8) ◽

pp. 1870-1878 ◽

Cited By ~ 4

Author(s):

Mingyue Hu ◽

Xiangxu Chen ◽

Li Ma ◽

Yu Ma ◽

Yuan Li ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Aerobic Glycolysis ◽

Malignant Phenotype ◽

Pancreatic Cancer Cells

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Everolimus regulates the activity of gemcitabine-resistant pancreatic cancer cells by targeting the Warburg effect via PI3K/AKT/mTOR signaling

Molecular Medicine ◽

10.1186/s10020-021-00300-8 ◽

2021 ◽

Vol 27 (1) ◽

Author(s):

Jing Cui ◽

Yao Guo ◽

Heshui Wu ◽

Jiongxin Xiong ◽

Tao Peng

Keyword(s):

Pancreatic Cancer ◽

Glucose Metabolism ◽

Cell Viability ◽

Cancer Cells ◽

Warburg Effect ◽

Aerobic Glycolysis ◽

Mtor Signaling ◽

Glucose Transporter 1 ◽

Pancreatic Cancer Cells ◽

The Warburg Effect

Abstract Background Gemcitabine (GEM) resistance remains a significant clinical challenge in pancreatic cancer treatment. Here, we investigated the therapeutic utility of everolimus (Evr), an inhibitor of mammalian target of rapamycin (mTOR), in targeting the Warburg effect to overcome GEM resistance in pancreatic cancer. Methods The effect of Evr and/or mTOR overexpression or GEM on cell viability, migration, apoptosis, and glucose metabolism (Warburg effect) was evaluated in GEM-sensitive (GEMsen) and GEM-resistant (GEMres) pancreatic cancer cells. Results We demonstrated that the upregulation of mTOR enhanced cell viability and favored the Warburg effect in pancreatic cancer cells via the regulation of PI3K/AKT/mTOR signaling. However, this effect was counteracted by Evr, which inhibited aerobic glycolysis by reducing the levels of glucose, lactic acid, and adenosine triphosphate and suppressing the expression of glucose transporter 1, lactate dehydrogenase-B, hexokinase 2, and pyruvate kinase M2 in GEMsen and GEMres cells. Evr also promoted apoptosis by upregulating the pro-apoptotic proteins Bax and cytochrome-c and downregulating the anti-apoptotic protein Bcl-2. GEM was minimally effective in suppressing GEMres cell activity, but the therapeutic effectiveness of Evr against pancreatic cancer growth was greater in GEMres cells than that in GEMsen cells. In vivo studies confirmed that while GEM failed to inhibit the progression of GEMres tumors, Evr significantly decreased the volume of GEMres tumors while suppressing tumor cell proliferation and enhancing tumor apoptosis in the presence of GEM. Conclusions Evr treatment may be a promising strategy to target the growth and activity of GEM-resistant pancreatic cancer cells by regulating glucose metabolism via inactivation of PI3K/AKT/mTOR signaling.

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Dickkopf-related protein 3 alters aerobic glycolysis in pancreatic cancer BxPC-3 cells, promoting CD4+ T-cell activation and function

European Journal of Medical Research ◽

10.1186/s40001-021-00567-x ◽

2021 ◽

Vol 26 (1) ◽

Author(s):

Qingqu Guo ◽

Yiming Chu ◽

Hongbo Li ◽

Dike Shi ◽

Lele Lin ◽

...

Keyword(s):

Pancreatic Cancer ◽

T Cells ◽

Glucose Uptake ◽

Cancer Cells ◽

T Cell Activation ◽

Therapeutic Potential ◽

Aerobic Glycolysis ◽

Related Protein ◽

Pancreatic Cancer Cells ◽

And Function

Abstract Background To investigate the value of Dickkopf-related protein 3 (DKK3) on aerobic glycolysis in pancreatic cancer cells, where DKK3-overexpression is used to determine its effects on CD4+ T cells. Methods The BxPC-3-DKK3 cell line was constructed, and peripheral blood mononuclear cell (PBMC) was prepared. After isolated the CD4+ T cells, the lactic acid, glucose uptake ability, cellular viability, proliferation, apoptosis, and markers were detected by PCR and western blot, and the concentrations of multiple cytokines were determined using the ELISA method. Results After co-culture with pancreatic cancer cells overexpressing DKK3, the glucose uptake markedly, proliferation enhanced and apoptosis inhibited in CD4+ T cells. The co-culture model also revealed that DKK3-overexpression promotes the activation and regulates the metabolism and function of CD4+ T cells. Conclusions DKK3 alters the metabolic microenvironment of pancreatic cancer cells and further facilitates the function of CD4+ T cells which suggesting that DKK3 may have a therapeutic potential in pancreatic cancer.

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Effect of Redd1 loss on proliferation and metastasis of pancreatic cancer cells with KrasG12D-LOH by inhibiting glycolysis.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15741 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15741-e15741

Author(s):

Mingyue Hu ◽

Peilin Huang ◽

Yu Ma ◽

Sunkai Ling ◽

Yuan Li ◽

...

Keyword(s):

Pancreatic Cancer ◽

Lactic Acid ◽

Cancer Cells ◽

Aerobic Glycolysis ◽

Genetically Engineered ◽

Mtor Pathway ◽

Kras Mutations ◽

Blank Group ◽

Pancreatic Cancer Cells ◽

Genetically Engineered Mice

e15741 Background: Aerobic glycolysis, regulated by mammalian target of rapamycin (mTOR) pathway, plays an important role in pancreatic carcinogenesis. Regulated in development and DNA damage response (Redd1) constitutes an important regulator of mTOR signaling. Previously, we observed that the loss of heterozygosity (LOH) status of Kras mutations (e.g. KrasG12D) is associated with an increased Redd1 expression. Here, we investigated the functional relevance of Redd1 in the context of KrasG12D-LOH. Methods: Murine KrasG12D-LOH/KrasG12Dpancreatic cancer cells isolated from genetically engineered mice were used in this study. The glycolysis dependence was detected by CCK8 assays after treated by glycolysis inhibitor 2-Deoxy-D-glucose (2-DG). Redd1 expression was down-regulated using shRNA transfection. Cell proliferation was determined by CCK8 and colony formation assays. Cell invasion and migration was measured by transwell and wound-healing assays. The levels of lactic acid and ATP were tested by ELISA kit. Genes related to glycolysis and mTOR signal were evaluated by western-blot and quantitative RT-PCR. Results: Compared with KRASG12D pancreatic cancer cells, the viability of KRASG12D-LOH cells decreased significantly in the presence of 2-DG. After Redd1 suppression, the proliferative and invasive potentials of KRASG12D-LOH cells decreased significantly when compared with blank group and negative group. The levels of lactic acid and ATP were also reduced by Redd1 down-regulation. Furthermore, the signal activity of mTOR pathway and Pkm2 and Hk2 expression were reduced dramatically, while Tsc1 and Tsc2 expression were unaffected. Conclusions: The LOH status of KRASG12D renders the pancreatic cancer cells additive to glycolysis, which further affect the proliferative and invasive potentials via the function of Redd1/mTOR. These data underscore the importance of KRASG12D-LOH in regulating cancer glucose metabolism.

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