AKR1C1 knock-down does not alter cell proliferation or response to chemotherapeutic agents in human hepatoma models

2021 ◽  
Author(s):  
Ismael Conceicao ◽  
Anastasia Arvaniti ◽  
Leanne Hodson ◽  
Nikolaos Nikolaou ◽  
Jeremy Tomlinson
Keyword(s):  
Cell Proliferation ◽  
Chemotherapeutic Agents ◽  
Human Hepatoma ◽  
Knock Down

The KLF6 Super Enhancer Modulates Cell Proliferation via MiR-1301 in Human Hepatoma Cells

MicroRNA ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 64-69 ◽  
Author(s):  
KumChol Ri ◽  
Chol Kim ◽  
CholJin Pak ◽  
PhyongChol Ri ◽  
HyonChol Om
Keyword(s):  
Cell Proliferation ◽  
Cellular Proliferation ◽  
Hepatoma Cells ◽  
Regulation Mechanism ◽  
Dependent Manner ◽  
Human Hepatoma ◽  
Human Hepatoma Cells ◽  
Over Expression ◽  
Super Enhancer ◽  
Engineering Changes

Background: Recent studies have attempted to elucidate the function of super enhancers by means of microRNAs. Although the functional outcomes of miR-1301 have become clearer, the pathways that regulate the expressions of miR-1301 remain unclear. Objective: The objective of this paper was to consider the pathway regulating expression of miR- 1301 and miR-1301 signaling pathways with the inhibition of cell proliferation. Methods: In this study, we prepared the cell clones that the KLF6 super enhancer was deleted by means of the CRISPR/Cas9 system-mediated genetic engineering. Changes in miR-1301 expression after the deletion of the KLF6 super enhancer were evaluated by RT-PCR analysis, and the signal pathway of miR-1301 with inhibition of the cell proliferation was examined using RNA interference technology. Results: The results showed that miR-1301 expression was significantly increased after the deletion of the KLF6 super enhancer. Over-expression of miR-1301 induced by deletion of the KLF6 super enhancer also regulated the expression of p21 and p53 in human hepatoma cells. functional modeling of findings using siRNA specific to miR-1301 showed that expression level changes had direct biological effects on cellular proliferation in Human hepatoma cells. Furthermore, cellular proliferation assay was shown to be directly associated with miR-1301 levels. Conclusion: As a result, it was demonstrated that the over-expression of miR-1301 induced by the disruption of the KLF6 super enhancer leads to a significant inhibition of proliferation in HepG2 cells. Moreover, it was demonstrated that the KLF6 super enhancer regulates the cell-proliferative effects which are mediated, at least in part, by the induction of p21and p53 in a p53-dependent manner. Our results provide the functional significance of miR-1301 in understanding the transcriptional regulation mechanism of the KLF6 super enhancer.

scholarly journals Sirtuin 2 in Endometrial Cancer: A Potential Regulator for Cell Proliferation, Apoptosis and RAS/ERK Pathway

2020 ◽  
Vol 19 ◽  
pp. 153303382098078
Author(s):  
Yanjuan Guo ◽  
Nannan Zhao ◽  
Jianli Zhou ◽  
Jianxin Dong ◽  
Xing Wang
Keyword(s):  
Cell Proliferation ◽  
Endometrial Cancer ◽  
Western Blot ◽  
Cell Line ◽  
Cell Lines ◽  
Erk Pathway ◽  
Uterine Epithelial Cell ◽  
Knock Down ◽  
Ishikawa Cells ◽  
And Control

Objective: The present study aimed to explore the function of sirtuin 2 (SIRT2) on cell proliferation, apoptosis, rat sarcoma virus (RAS)/ extracellular signal-regulated kinase (ERK) pathway in endometrial cancer (EC). Methods: SIRT2 expression in human EC cell lines and human endometrial (uterine) epithelial cell (HEEC) line was assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot. SIRT2 knock-down and control knock-down plasmids were transfected into HEC1A cells, respectively; SIRT2 overexpression and control overexpression plasmids were transfected into Ishikawa cells, respectively. After transfection, SIRT2, HRas proto-oncogene, GTPase (HRAS) expressions were evaluated by RT-qPCR and western blot. ERK and phosphorylated ERK (pERK) expressions were evaluated by western blot. Meanwhile, cell proliferation and cell apoptosis were measured. Results: Compared to normal HEEC cell line, SIRT2 mRNA and protein expressions were increased in most human EC cell lines (including HEC1A, RL952 and AN3CA), while were similar in Ishikawa cell line. In HEC1A cells, SIRT2 knock-down decreased cell proliferation but increased apoptosis. In Ishikawa cells, SIRT2 overexpression induced cell proliferation but inhibited apoptosis. For RAS/ERK pathway, SIRT2 knock-down reduced HRAS and inactivated pERK in HEC1A cells, whereas SIRT2 overexpression increased HRAS and activated pERK in Ishikawa cells, suggesting that SIRT2 was implicated in the regulation of RAS/ERK pathway in EC cells. Conclusion: SIRT2 contributes to the EC tumorigenesis, which appears as a potential therapeutic target.

Erythropoietin: Physiology and Pharmacology Update

2003 ◽  
Vol 228 (1) ◽  
pp. 1-14 ◽  
Author(s):  
James W. Fisher
Keyword(s):  
Cell Proliferation ◽  
Renal Failure ◽  
Chronic Renal Failure ◽  
Receptor Activation ◽  
Chemotherapeutic Agents ◽  
Phospholipase A ◽  
Cell Surface Receptor ◽  
Erythroid Progenitor ◽  
Epo Receptor ◽  
Stimulation Of

This minireview is an update of a 1997 review on erythropoletin (EPO) in this journal (1). EPO is a 30,400-dalton glycoprotein that regulates red cell production. In the human, EPO is produced by peritubular cells in the kidneys of the adult and in hepatocytes in the fetus. Small amounts of extra-renal EPO are produced by the liver in adult human subjects. EPO binds to an erythroid progenitor cell surface receptor that includes a p66 chain, and, when activated, the p66 protein becomes dimerized. EPO receptor activation induces a JAK2 tyrosine kinase, which leads to tyrosine phosphorylation of the EPO receptor and several proteins. EPO receptor binding leads to intracellular activation of the Ras/mitogen-activated kinase pathway, which is involved with cell proliferation, phosphatidylinositol 3-kinase, and STATS 1, 3, 5A, and 5B transcriptional factors. EPO acts primarily to rescue erythroid cells from apoptosis (programmed cell death) to increase their survival. EPO acts synergistically with several growth factors (SCF, GM-CSF, 1L-3, and IGF-1) to cause maturation and proliferation of erythroid progenitor cells (primarily colony-forming unit-E). Oxygen-dependent regulation of EPO gene expression is postulated to be controlled by a hypoxia-inducible transcription factor (HIF-1α). Hypoxia-inducible EPO production is controlled by a 50-bp hypoxia-inducible enhancer that is approximately 120 bp 3' to the polyadenylation site. Hypoxia signal transduction pathways involve kinases A and C, phospholipase A2, and transcription factors ATF-1 and CREB-1. A model has been proposed for adenosine activation of EPO production that involves protein kinases A and C and the phospholipase A2 pathway. Other effects of EPO include a hematocrit-independent, vasoconstriction-dependent hypertension, increased endothelin production, upregulation of tissue renin, change in vascular tissue prostaglandins production, stimulation of angiogenesis, and stimulation of endothelial and vascular smooth muscle cell proliferation. Recombinant human EPO (rHuEPO) is currently being used to treat patients with anemias associated with chronic renal failure, AIDS patients with anemia due to treatment with zidovudine, nonmyeloid malignancies in patients treated with chemotherapeutic agents, perioperative surgical patients, and autologous blood donation. A novel erythropolesis-stimulating factor (NESP, darbepoetin) has been synthesized and when compared with rHuEPO, NESP has a higher carbohydrate content (52% vs 40%), a longer plasma half-life, the amino acid sequence differs from that of native human EPO at five positions, and has been reported to maintain hemoglobin levels just as effectively in patients with chronic renal failure as rHuEPO at less frequent dosing. The use of rHuEPO and darbepoetin to enhance athletic performance is officially banned by most sports-governing bodies because the excessive erythrocytosis can lead to increased thrombogenicity and can cause deep vein, coronary, and cerebral thromboses.

Targeted Modulation of FAK/PI3K/PDK1/AKT and FAK/p53 Pathways by Cucurbitacin B for the Antiproliferation Effect Against Human Cholangiocarcinoma Cells

2020 ◽  
Vol 48 (06) ◽  
pp. 1475-1489
Author(s):  
Sirinapha Klungsaeng ◽  
Veerapol Kukongviriyapan ◽  
Auemduan Prawan ◽  
Sarinya Kongpetch ◽  
Laddawan Senggunprai
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Inhibitory Effect ◽  
Chemotherapeutic Agents ◽  
Cucurbitacin B ◽  
M Phase ◽  
Cell Cycle Disruption

Inadequate responses to traditional chemotherapeutic agents in cholangiocarcinoma (CCA) emphasize a requirement for new effective compounds for the treatment of this malignancy. This study aimed to investigate the antiproliferative property of cucurbitacin B on KKU-100 CCA cells. The determination of underlying molecular mechanisms was also carried out. The results revealed that cucurbitacin B suppressed growth and replicative ability to form colonies of CCA cells, suggesting the antiproliferative effect of this compound against the cells. Flow cytometry analysis demonstrated that the interfering effect of cucurbitacin B on the CCA cell cycle at the G2/M phase was accountable for its antiproliferation property. Accompanied with cell cycle disruption, cucurbitacin B altered the expression of proteins involved in the G2/M phase transition including downregulation of cyclin A, cyclin D1, and cdc25A, and upregulation of p21. Additional molecular studies demonstrated that cucurbitacin B suppressed the activation of focal adhesion kinase (FAK) which consequently resulted in inhibition of its kinase-dependent and kinase-independent downstream targets contributing to the regulation of cell proliferation including PI3K/PDK1/AKT and p53 proteins. In this study, the transient knockdown of FAK using siRNA was employed to ascertain the role of FAK in CCA cell proliferation. Finally, the effect of cucurbitacin B on upstream receptor tyrosine kinases regulating FAK activation was elucidated. The results showed that the inhibitory effect of cucurbitacin B on FAK activation in CCA cells is mediated via interference of EGFR and HER2 expression. Collectively, cucurbitacin B might be a promising drug for CCA treatment by targeting FAK protein.

scholarly journals Characteristics of Cell Proliferation in Four Patients with Untreated Acute Leukemia

Blood ◽  
1966 ◽  
Vol 28 (3) ◽  
pp. 428-445 ◽  
Author(s):  
ALVIN M. MAUER ◽  
VIRGINIA FISHER
Keyword(s):  
Cell Proliferation ◽  
Cell Division ◽  
Acute Leukemia ◽  
Generation Time ◽  
Chemotherapeutic Agents ◽  
Leukemic Cells ◽  
Dividing Cells ◽  
Almost All

Abstract The characteristics of proliferation of leukemic cells in four children with untreated acute leukemia have been studied. In all four of these children a population of marrow leukemic cells was found which were dividing with a generation time of about 15 to 20 hours. In two of these patients it was possible to demonstrate that these dividing cells after one or more mitotic divisions became smaller and stopped dividing. In all of these patients 70 per cent or more of the leukemic cells of the marrow and almost all leukemic cells of the blood were nonproliferative at the time of these studies. These nondividing cells would be relatively unaffected by chemotherapeutic agents designed to inhibit cell division.

scholarly journals Neochamaejasmin A Induces Mitochondrial-Mediated Apoptosis in Human Hepatoma Cells via ROS-Dependent Activation of the ERK1/2/JNK Signaling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Yangfang Ding ◽  
Qi Xie ◽  
Wenjing Liu ◽  
Zhaohai Pan ◽  
Xinmei Fan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Signaling Pathway ◽  
Cell Apoptosis ◽  
Hepg2 Cells ◽  
Morphological Changes ◽  
Control Group ◽  
Dependent Manner ◽  
Human Hepatoma ◽  
Jnk Signaling ◽  
Jnk Signaling Pathway

The botanical constituents of Stellera chamaejasme Linn. exhibit various pharmacological and medicinal activities. Neochamaejasmin A (NCA), one main active constituent of S. chamaejasme, inhibits cell proliferation and induces cell apoptosis in several types of tumor cells. However, the antitumor effect of NCA on hepatocellular carcinoma cells is still unclear. In this study, NCA (36.9, 73.7, and 147.5 μM) significantly inhibited hepatoblastoma-derived HepG2 cell proliferation in a concentration-dependent manner. Hoechst 33258 staining and flow cytometry showed that apoptotic morphological changes were observed and the apoptotic rate was significantly increased in NCA-treated HepG2 cells, respectively. Additionally, the levels of Bax, cleaved caspase-3, and cytoplasmic cytochrome c were increased, while the level of Bcl-2 was decreased in NCA-treated HepG2 cells when compared with the control group. Moreover, we found that the reactive oxygen species (ROS) level was significantly higher and the mitochondrial membrane potential was remarkably lower in NCA-treated HepG2 cells than in the control group. Further studies demonstrated that the levels of p-JNK and p-ERK1/2 were significantly upregulated in NCA-treated HepG2 cells, and pretreatment with JNK and ERK1/2 inhibitors, SP600125 and PD0325901, respectively, suppressed NCA-induced cell apoptosis of HepG2 cells. In addition, NCA also significantly inhibited human hepatoma BEL-7402 cell proliferation and induced cell apoptosis through the ROS-mediated mitochondrial apoptotic pathway. These results implied that NCA induced mitochondrial-mediated cell apoptosis via ROS-dependent activation of the ERK1/2/JNK signaling pathway in HepG2 cells.

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