scholarly journals Targeting Pyruvate Kinase M2 and Lactate Dehydrogenase A Is an Effective Combination Strategy for the Treatment of Pancreatic Cancer

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1372 ◽  
Author(s):  
Goran Hamid Mohammad ◽  
Vessela Vassileva ◽  
Pilar Acedo ◽  
Steven W. M. Olde Damink ◽  
Massimo Malago ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Enzyme Activity ◽  
Lactate Dehydrogenase ◽  
Tumor Growth ◽  
Pyruvate Kinase ◽  
Glycolytic Enzymes ◽  
Pyruvate Kinase M2 ◽  
Tumor Tissues

Reprogrammed glucose metabolism is one of the hallmarks of cancer, and increased expression of key glycolytic enzymes, such as pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA), has been associated with poor prognosis in various malignancies. Targeting these enzymes could attenuate aerobic glycolysis and inhibit tumor proliferation. We investigated whether the PKM2 activator, TEPP-46, and the LDHA inhibitor, FX-11, can be combined to inhibit in vitro and in vivo tumor growth in preclinical models of pancreatic cancer. We assessed PKM2 and LDHA expression, enzyme activity, and cell proliferation rate after treatment with TEPP-46, FX-11, or a combination of both. Efficacy was validated in vivo by evaluating tumor growth, PK and LDHA activity in plasma and tumors, and PKM2, LDHA, and Ki-67 expression in tumor tissues following treatment. Dual therapy synergistically inhibited pancreatic cancer cell proliferation and significantly delayed tumor growth in vivo without apparent toxicity. Treatment with TEPP-46 and FX-11 resulted in increased PK and reduced LDHA enzyme activity in plasma and tumor tissues and decreased PKM2 and LDHA expression in tumors, which was reflected by a decrease in tumor volume and proliferation. The targeting of glycolytic enzymes such as PKM2 and LDHA represents a promising therapeutic approach for the treatment of pancreatic cancer.

2′-hydroxycinnamaldehyde inhibits cancer cell proliferation and tumor growth by targeting the pyruvate kinase M2

2018 ◽  
Vol 434 ◽  
pp. 42-55 ◽  
Author(s):  
Yae Jin Yoon ◽  
Young-Hwan Kim ◽  
Yena Jin ◽  
Seung-Wook Chi ◽  
Jeong Hee Moon ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Pyruvate Kinase ◽  
Cancer Cell ◽  
Cancer Cell Proliferation ◽  
Pyruvate Kinase M2

scholarly journals Positive feedback between lncRNA FLVCR1-AS1 and KLF10 may inhibit pancreatic cancer progression via the PTEN/AKT pathway

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Jiewei Lin ◽  
Shuyu Zhai ◽  
Siyi Zou ◽  
Zhiwei Xu ◽  
Jun Zhang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Positive Feedback ◽  
Molecular Mechanisms ◽  
Tumor Tissues ◽  
And Migration

Abstract Background FLVCR1-AS1 is a key regulator of cancer progression. However, the biological functions and underlying molecular mechanisms of pancreatic cancer (PC) remain unknown. Methods FLVCR1-AS1 expression levels in 77 PC tissues and matched non-tumor tissues were analyzed by qRT-PCR. Moreover, the role of FLVCR1-AS1 in PC cell proliferation, cell cycle, and migration was verified via functional in vitro and in vivo experiments. Further, the potential competitive endogenous RNA (ceRNA) network between FLVCR1-AS1 and KLF10, as well as FLVCR1-AS1 transcription levels, were investigated. Results FLVCR1-AS1 expression was low in both PC tissues and PC cell lines, and FLVCR1-AS1 downregulation was associated with a worse prognosis in patients with PC. Functional experiments demonstrated that FLVCR1-AS1 overexpression significantly suppressed PC cell proliferation, cell cycle, and migration both in vitro and in vivo. Mechanistic investigations revealed that FLVCR1-AS1 acts as a ceRNA to sequester miR-513c-5p or miR-514b-5p from the sponging KLF10 mRNA, thereby relieving their suppressive effects on KLF10 expression. Additionally, FLVCR1-AS1 was shown to be a direct transcriptional target of KLF10. Conclusions Our research suggests that FLVCR1-AS1 plays a tumor-suppressive role in PC by inhibiting proliferation, cell cycle, and migration through a positive feedback loop with KLF10, thereby providing a novel therapeutic strategy for PC treatment.

Comparative study of free and bound glycolytic enzymes from sea scorpion brain

1998 ◽  
Vol 76 (4) ◽  
pp. 609-614 ◽  
Author(s):  
Volodymyr I Lushchak ◽  
Ljudmyla P Lushchak ◽  
Tetjana V Bahnjukova ◽  
Alexei V Spichenkov ◽  
Kenneth B Storey
Keyword(s):  
Lactate Dehydrogenase ◽  
Pyruvate Kinase ◽  
Substrate Inhibition ◽  
Physiological Role ◽  
Glycolytic Enzymes ◽  
Free Form ◽  
Hill Coefficients ◽  
Low Ionic Strength ◽  
Scorpaena Porcus

Free and bound forms of hexokinase, pyruvate kinase, and lactate dehydrogenase were prepared from the brain of the sea scorpion (Scorpaena porcus) in a low ionic strength medium. Properties of the free and bound forms were compared to determine whether binding to particulate matter could influence enzyme function or stability in vivo. Changes in pH differently affected the activity of the free and bound forms of all three enzymes. Furthermore, bound forms of hexokinase and pyruvate kinase were more stable than the free enzymes to heating at 45°C. Bound hexokinase showed higher affinity for substrates (ATP, glucose) than the free form and bound lactate dehydrogenase had greater affinity for pyruvate and NADH. Although the affinities of the two forms of pyruvate kinase for substrates were similar, Hill coefficients for phosphoenolpyruvate as well as inhibition by ATP differed between the two enzyme forms. Free and bound lactate dehydrogenase also showed differences in Hill coefficients and bound lactate dehydrogenase was less sensitive to substrate inhibition by high pyruvate concentrations. The possible physiological role of the binding of these glycolytic enzymes to subcellular structures is discussed.Key words: hexokinase, lactate dehydrogenase, pyruvate kinase, enzyme binding, Scorpaena porcus.

scholarly journals Endometrial pyruvate kinase M2 is essential for decidualization during early pregnancy

2020 ◽  
Vol 245 (3) ◽  
pp. 357-368 ◽  
Author(s):  
Yan Su ◽  
Sujuan Guo ◽  
Chunyan Liu ◽  
Na Li ◽  
Shuang Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pyruvate Kinase ◽  
Early Pregnancy ◽  
Stromal Cells ◽  
Embryo Implantation ◽  
Pyruvate Kinase M2 ◽  
Ishikawa Cells ◽  
Implantation Sites

Embryo implantation is essential for normal pregnancy. Decidualization is known to facilitate embryo implantation and maintain pregnancy. Uterine stromal cells undergo transformation into decidual cells after embryo attachment to the endometrium. Pyruvate kinase M2 (PKM2) is a rate limiting enzyme in the glycolysis process which catalyzes phosphoenolpyruvic acid into pyruvate. However, little is known regarding the role of PKM2 during endometrial decidualization. In this study, PKM2 was found to be mainly located in the uterine glandular epithelium and luminal epithelium on day 1 and day 4 of pregnancy and strongly expressed in the decidual zone after embryo implantation. PKM2 was dramatically increased with the onset of decidualization. Upon further exploration, PKM2 was found to be more highly expressed at the implantation sites than at the inter-implantation sites on days 5 to 7 of pregnancy. PKM2 expression was also significantly increased after artificial decidualization both in vivo and in vitro. After PKM2 expression was knocked down by siRNA, the number of embryo implantation sites in mice on day 7 of pregnancy was significantly reduced, and the decidualization markers BMP2 and Hoxa10 were also obviously downregulated in vivo and in vitro. Downregulated PKM2 could also compromise cell proliferation in primary endometrial stromal cells and in Ishikawa cells. The migration rate of Ishikawa cells was also obviously suppressed by si-PKM2 according to the wound healing assay. In conclusion, PKM2 might play an important role in decidualization during early pregnancy, and cell proliferation might be one pathway for PKM2 regulated decidualization.

scholarly journals circZMYM2 Competed Endogenously with miR-335-5p to Regulate JMJD2C in Pancreatic Cancer

2018 ◽  
Vol 51 (5) ◽  
pp. 2224-2236 ◽  
Author(s):  
Yong An ◽  
Huihua Cai ◽  
Yue Zhang ◽  
Shengyong Liu ◽  
Yunfei Duan ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Underlying Mechanism ◽  
Luciferase Reporter ◽  
Tissue Samples ◽  
Paired Normal Tissue ◽  
Reporter Assays ◽  
Induced Apoptosis

Background/Aims: We aimed to study the involvement of circZMYM2 (hsa_circ_0099999) in pancreatic cancer (PC) cell proliferation, apoptosis and invasion and to figured out the underlying mechanism of circZMYM2 regulating miR-335-5p and JMJD2C. Methods: CircRNA differential expressions in twenty PC samples and paired normal tissue samples were analyzed using Arraystar Human CircRNA microarray V1. CircZMYM2 expression level was determined via qRT-PCR. The effects of circZMYM2 inhibition and overexpression on cell proliferation, cell apoptosis and cell invasion were investigated by CCK-8 assays, Flow cytometry assays and Transwell assays. An animal experiment on nude mice was put forward to test the influence of circZMYM2 knockdown on tumor growth. The relationship between circZMYM2, miR-335 and JMJD2C was verified by RNA pull down, dual-luciferase reporter assays and rescue experiment. The effect of circZMYM2 and miR-335-5p on the expression of JMJD2C protein was detected by western blot. Results: CircZMYM2 overexpression was observed in both PC tissues and cells. Knockdown of circZMYM2 inhibited proliferation, induced apoptosis, and weakened invasion ability of cancer cells. Tumor growth was restrained in vivo. CircZMYM2 repressed the expression of its target miR-335-5p. MiR-335-5p attenuated pancreatic cancer development via inhibition of JMJD2C. Conclusion: Our study demonstrated that circZMYM2 promoted PC progression. CircZMYM2 had a sponge effect on miR-335-5p and modulated the downstream oncogene JMJD2C.

scholarly journals The brush border of rabbit kidney, a cellular compartment free of glycolytic enzymes

1978 ◽  
Vol 174 (2) ◽  
pp. 509-515 ◽  
Author(s):  
Dietrich Busse ◽  
Hans Ulrich Wahle ◽  
Harald Bartel ◽  
Barbara Pohl
Keyword(s):  
Lactate Dehydrogenase ◽  
Pyruvate Kinase ◽  
Brush Border ◽  
Gradient Centrifugation ◽  
Fluorescein Isothiocyanate ◽  
Glycolytic Enzymes ◽  
Rabbit Kidney ◽  
Cellular Compartment ◽  
Fluorescein Isothiocyanate Dextran

Activities of four enzymes of the glycolytic pathway, hexokinase, glyceraldehyde 3-phosphate dehydrogenase, pyruvate kinase and lactate dehydrogenase, were determined in a vesicular brush-border preparation from rabbit kidneys. The specific activities of the enzymes were decreased several-hundredfold in the brush-border preparation compared with a kidney homogenate, but the enzymes were not totally absent. Density-gradient centrifugation of the brush-border preparation yielded brush border of even higher purity and also a characteristic pattern of distribution for each of the contaminating intracellular membranes. The presence of hexokinase in the brush-border preparation could be traced to contaminating mitochondria, and that of glyceraldehyde 3-phosphate dehydrogenase, pyruvate kinase and lactate dehydrogenase to contaminating vesicles derived from the endoplasmic reticulum. The brush-border vesicles contained some ATP. An intravesicular concentration of 0.1mm was estimated, indicating that the vesicles had retained at least a part of their original content. Experiments in which fluorescein isothiocyanate-dextran (mol.wt. 20000) was present during cell lysis revealed that much, but not all, of the brush-border contents had been exchanged with the medium. The complete absence of glycolytic enzymes from brush-border vesicles, which had retained part of their original content, indicates that the brush border does not contain glycolytic enzymes in vivo and can be thought of as a compartment of its own, somehow separated from the cytoplasm.

scholarly journals Fibroblast Growth Factor 11 (FGF11) Promotes Non-small Cell Lung Cancer (NSCLC) Progression by Regulating Hypoxia Signaling Pathway

2021 ◽  
Author(s):  
Xiaowei Wu ◽  
Minjie Li ◽  
Yu Deng ◽  
Shun Ke ◽  
Fan Li ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Growth ◽  
Signaling Pathway ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Normal Tissues ◽  
Tumor Tissues ◽  
Hypoxia Signaling

Abstract Background: Recently, accumulating studies highlight the critical regulatory roles of fibroblast growth factors (FGF), and a series of FGF, participated in the progression of multiple human cancers, including non-small cell lung cancer (NSCLC). Methods: Gene transcriptome analysis was used to identify the differential expression of FGF11 in NSCLC tumor tissues, GSE75037 and GSE81089 database analysis was performed on NSCLC tumor tissues and adjacent normal tissues to validate the expression of FGF11. Then, we selected 100 cases of NSCLC tumor tissues and 30 cases of matched adjacent normal tissues to confirm the mRNA and protein level of FGF11 by qRT-PCR and immunohistochemistry. Bioinformatics analysis and dual luciferase reporter analysis was also performed to examine the direct regulatory of FGF11 by miR-525-5p. CCK-8 and transwell assay was also performed to detect the cell proliferation, migration and invasion. Signal pathway analysis was also investigated the effect of FGF11 on NSCLC cell proliferation was associated with the hypoxia signaling pathway. The role of FGF11 in NSCLC tumor growth was further explored by in vivo study.Results: FGF11 was overexpressed in NSCLC tumor tissues and tumor cell lines, the high expression of FGF11 was closely associated with poor overall survival of NSCLC patients. In vitro loss- and gain- of function experiments demonstrated that FGF11 knockdown inhibited, whereas FGF11 overexpression promoted the proliferation, migration and invasion of NSCLC cells. The dual luciferase reporter assay confirmed that FGF11 was downregulated by miR-525-5p, and the effect of FGF11 on cell proliferation, migration and invasion could be interfered by miR-525-5p. We further found that FGF11 had significant correlation with hypoxia signaling pathway activation, meanwhile regulating HIF-1α. Further experiments implicated that the oncogenic role of FGF11 could be blocked via interfering of HIF-1α in NSCLC cells. Moreover, knockdown of FGF11 suppressed NSCLC tumor growth whereas overexpression of FGF11 promoted tumor growth in vivo. Conclusions: FGF11 might be functioned as an oncogene in tumor development, the findings of our study revealed a novel regulatory mechanism of FGF11 involved in hypoxia signaling pathway, which offers novel strategies for the treatment of NSCLC.

scholarly journals Pyruvate Kinase M2 and Lactate Dehydrogenase A Are Overexpressed in Pancreatic Cancer and Correlate with Poor Outcome

PLoS ONE ◽  
2016 ◽  
Vol 11 (3) ◽  
pp. e0151635 ◽  
Author(s):  
Goran Hamid Mohammad ◽  
S. W. M. Olde Damink ◽  
Massimo Malago ◽  
Dipok Kumar Dhar ◽  
Stephen P. Pereira
Keyword(s):  
Pancreatic Cancer ◽  
Lactate Dehydrogenase ◽  
Pyruvate Kinase ◽  
Pyruvate Kinase M2 ◽  
Poor Outcome

scholarly journals Silencing of PSMC2 inhibits development and metastasis of prostate cancer through regulating proliferation, apoptosis and migration

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Qingke Chen ◽  
Lingmin Fu ◽  
Jieping Hu ◽  
Guanghua Guo ◽  
An Xie
Keyword(s):  
Prostate Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Migration ◽  
Tumor Growth ◽  
Colony Formation ◽  
26S Proteasome ◽  
Tumor Tissues ◽  
Xenograft Models

Abstract Background Prostate cancer is the most common malignant tumor of male genitourinary system, molecular mechanism of which is still not clear. PSMC2 (proteasome 26S subunit ATPase 2) is a key member of the 19S regulatory subunit of 26S proteasome, whose relationship with prostate cancer is rarely studied. Methods Here, expression of PSMC2 in tumor tissues or cells of prostate cancer was detected by qPCR, western blotting and immunohistochemical analysis. The effects of PSMC2 knockdown on cell proliferation, colony formation, cell migration, cell cycle and apoptosis were assessed by Celigo cell counting assay, colony formation assay, wound-healing assay, Transwell assay and flow cytometry, respectively. The influence of PSMC2 knockdown on tumor growth in vivo was evaluated by mice xenograft models. Results The results demonstrated that PSMC2 was upregulated in tumor tissues of prostate cancer and its high expression was significantly associated with advanced Gleason grade and higher Gleason score. Knockdown of PSMC2 could inhibited cell proliferation, colony formation and cell migration of prostate cancer cells, while promoting cell apoptosis and cell cycle arrest. The suppression of tumor growth in vivo by PSMC2 knockdown was also showed by using mice xenograft models. Moreover, the regulation of prostate cancer by PSMC2 may be mediated by Akt/Cyclin D1/CDK6 signaling pathway. Conclusions Therefore, our studies suggested that PSMC2 may act as a tumor promotor in the development and progression of prostate cancer, and could be considered as a novel therapeutic target for prostate cancer treatment.

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