scholarly journals Nuclear upregulation of PI3K p110β correlates with increased rRNA transcription in endometrial cancer cells

2019 ◽  
Author(s):  
Fatemeh Mazloumi Gavgani ◽  
Thomas Karlsson ◽  
Ingvild L Tangen ◽  
Andrea Papdiné Morovicz ◽  
Victoria Smith Arnesen ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Pi3k Pathway ◽  
Clinical Samples ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Cytoplasmic Staining ◽  
Ec Cells

AbstractGenes encoding for components of the phosphoinositide 3-kinase (PI3K) pathway are frequently mutated in cancer, including inactivating mutations of PTEN and activating mutations of PIK3CA, encoding the PI3K catalytic subunit p110α. PIK3CB, encoding p110β, is rarely mutated, but can contribute to tumourigenesis in some PTEN-deficient tumours. The underlying molecular mechanisms are however poorly understood. By analysing cell lines and annotated clinical samples, we have previously found that p110β is highly expressed in endometrial cancer (EC) cell lines and that PIK3CB mRNA levels increase early in primary tumours correlating with lower survival. Selective inhibition of p110α and p110β led to different effects on cell signalling and cell function, p110α activity being correlated to cell survival in PIK3CA mutant cells and p110β with cell proliferation in PTEN-deficient cells. To understand the mechanisms governing the differential roles of these isoforms, we assessed their sub-cellular localisation. p110α was cytoplasmic whereas p110β was both cytoplasmic and nuclear with increased levels in both compartments in cancer cells. Immunohistochemistry of p110β in clinically annotated patient tumour sections revealed high nuclear/cytoplasmic staining ratio, which correlated significantly with higher grades. Consistently, the presence of high levels of p110β in the nuclei of EC cells, correlated with high levels of its product phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) in the nucleus. Using immunofluorescence labelling, we observed both p110β and PtdIns(3,4,5)P3 in the nucleoli of EC cell lines. The production of nucleolar PtdIns(3,4,5)P3 was dependent upon p110β activity. EC cells with high levels of nuclear PtdIns(3,4,5)P3 and p110β showed elevated nucleolar activity as assessed by the increase in 47S pre-rRNA transcriptional levels in a p110β-dependent manner. Altogether, these results present a nucleolar role for the PI3K pathway that may contribute to tumour progression in endometrial cancer.

Momordica charantia Seed and Aryl Extracts Potentiate Growth Inhibition and Apoptosis by Dual Blocking of PI3K/AKT and MAPK Pathways as a Downstream Target of EGFR Signaling in Breast Cancer Cells

2020 ◽  
Vol 16 (5) ◽  
pp. 726-733
Author(s):  
Guzide Satir Basaran ◽  
Hatice Bekci ◽  
Ayse Baldemir ◽  
Selen Ilgun ◽  
Ahmet Cumaoglu
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Momordica Charantia ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Seed Extracts

Background and Objective: Herbal extracts and plant compounds are increasingly becoming of interest for their therapeutic potential in various cancer types. Momordica charantia is well known for its anti-diabetic, anti-inflammatory, and anti-cancer properties. Methods: In the present study, we investigated the antiproliferative and pro-apoptotic effects of Momordica charantia seed and aryl extracts on breast cancer cells and explored the underlying molecular mechanisms. Results: Our results showed that both extract significantly inhibited the growth of MCF-7 and MDA MB-231 cells in a concentration-dependent manner, and induced apoptosis by upregulation of caspase 9 and caspase 3 mRNA levels. In addition, in different incubation time, both extract evidently inhibited EGF and induced EGFR phosphorylation/activation in both cell lines. Moreover, Momordica charantia aryl and seed extracts inhibited phosphorylation/activation of PI3K/AKT and MAPK (ERK and P38) pathways in both cell lines. Conclusion: The current study clearly demonstrates that the Momordica charantia aryl and seed extracts have the potential to exert its cytotoxic effect on breast cancer cells by a mechanism involving inhibition of EGFR and EGRF related pathways with the induction of apoptosis. The overall finding demonstrates that this plant, especially seed extract, could be a potential source of new anticancer compounds for possible drug development against cancer.

Targeting RNF8 Effectively Reverse Cisplatin and Doxorubicin Resistance in Endometrial Cancer

2020 ◽  
Author(s):  
Ben Yang ◽  
Wang Ke ◽  
Yingchun Wan ◽  
Tao Li
Keyword(s):  
Endometrial Cancer ◽  
Cell Lines ◽  
Quantitative Polymerase Chain Reaction ◽  
Mrna Levels ◽  
Mice Model ◽  
Expression Levels ◽  
Gynecological Malignancy ◽  
Ec Cells

Abstract Background Endometrial cancer (EC) is one of the most frequent gynecological malignancy worldwide. However, resistance to chemotherapy remains one of the major difficulties in the treatment of EC. Thus, there is an urgent requirement to understand mechanisms of chemoresistance and identify novel regimens for patients with EC. Methods Cisplatin and doxorubicin resistant cell lines were acquired by continuous exposing parental EC cells to cisplatin or doxorubicin for 3 months. Cell viability was determined by using MTT assay. Protein Expression levels of protein were examined by western blotting assay. mRNA levels were measured by quantitative polymerase chain reaction (qPCR) assay. Ring finger protein 8 (RNF8) knockout cell lines were generated by clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9 gene editing assay. Nonhomologous end joining (NHEJ) efficiency were quantified by plasmid based NHEJ assay. DNA double strand breaks (DSB) were generated using laser micro-irradiation. Protein recruitment to DSB was analyzed by immunofluorescent assay. Tumor growth was examined by AN3CA xenograft mice model. Results We found that protein and mRNA expression levels of RNF8 were significantly increased in both cisplatin and doxorubicin resistant EC cells. Cell survival assay showed that RNF deficiency significantly enhanced the sensitivity of resistant EC cells to cisplatin and doxorubicin (P < 0.01). In addition, chemoresistant EC cells exhibited increased NHEJ efficiency. Knockout of RNF8 in chemoresistant EC cells significantly reduced NHEJ efficiency and prolonged Ku80 retention on DSB. Moreover, cisplatin resistant AN3CA xenograft showed that RNF8 deficiency overcame cisplatin resistance. Conclusions Our in vitro and in vivo assays provide evidence for RNF8, which is a NHEJ factor, serving as a promising, novel target in EC chemotherapy.

scholarly journals The antagonistic regulation of human MUC4 and ErbB-2 genes by the Ets protein PEA3 in pancreatic cancer cells: implications for the proliferation/differentiation balance in the cells

2005 ◽  
Vol 386 (1) ◽  
pp. 35-45 ◽  
Author(s):  
Valérie FAUQUETTE ◽  
Michael PERRAIS ◽  
Sylvain CERULIS ◽  
Nicolas JONCKHEERE ◽  
Marie-Paule DUCOUROUBLE ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Biological Marker ◽  
Proximal Region ◽  
Site Directed Mutagenesis ◽  
Tyrosine Kinase Receptor ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Pancreatic Cancer Cells

The human transmembrane mucin MUC4 is aberrantly expressed in 75% of pancreatic ductal adenocarcinomas, whereas no expression is found in normal pancreas. Therefore MUC4 appears as a useful biological marker for the diagnosis of ductal adenocarcinomas. Since rat Muc4 was shown to interact with ErbB-2 tyrosine kinase receptor and to either promote cell survival and differentiation or cell proliferation, it is postulated that MUC4 may also participate in pancreatic carcinogenesis. Our aim was to investigate in parallel the role of the Ets factor PEA3 in MUC4 and ErbB-2 transcriptional regulation in pancreatic cancer cells. Two MUC4-expressing WD (well-differentiated) (CAPAN-1 and -2) and one MUC4-non-expressing poorly differentiated (PANC-1) cell lines were used. The three cell lines express ErbB-2 at different levels. By co-transfection and site-directed mutagenesis, we show that PEA3 is a transactivator of the MUC4 promoter and that the −216 and −2368 PEA3 binding sites of the MUC4 promoter are essential. We also demonstrate that PEA3 acts in synergy with c-Jun and specificity protein 1 to transactivate the proximal region of the MUC4 promoter and increase MUC4 mRNA levels in WD cells. These results suggest that MUC4 is a new target gene of the Ets factor PEA3 in pancreatic cancer cells. In contrast, PEA3 represses the transcriptional activity of two fragments of the ErbB-2 promoter in a dose-dependent manner and decreases the endogenous ErbB-2 mRNA levels in WD cell lines. Thus, PEA3, by its capacity to up-regulate the epithelial marker MUC4 and to down-regulate the ErbB-2 oncogene, appears as a key regulator of the differentiation/proliferation balance in pancreatic cancer cells.

scholarly journals Psiadin and plectranthone selectively inhibit colorectal carcinoma cells proliferation via modulating cyclins signaling and apoptotic pathways

PLoS ONE ◽  
2021 ◽  
Vol 16 (6) ◽  
pp. e0252820
Author(s):  
Khaled Y. Orabi ◽  
Mohamed S. Abaza ◽  
Yunus A. Luqmani ◽  
Rajaa Al-Attiyah
Keyword(s):  
Colorectal Carcinoma ◽  
Cancer Cells ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Normal Breast ◽  
Dependent Manner ◽  
Isolation And Purification ◽  
Apoptotic Pathways ◽  
Dose Dependent

Three scarce terpenes, psiadin, plectranthone and saudinolide, were obtained after chromatographic isolation and purification from the aerial parts of the respective plants. Their identities were established based on their spectral data. Their anticancer effects against two human colorectal carcinoma cell lines, CCL233 and CCL235, along with the potential molecular mechanisms of action, were explored. Psiadin and plectranthone exhibited marked growth inhibition on both cell lines in a time- and dose-dependent manner with minimal cytotoxicity against normal breast cells (HB2). The terpenes even showed superior activities to the tested standards. Flow cytometry showed apoptosis induction and alteration in the cell cycle in colorectal cancer cells treated with both compounds. Nevertheless, it was also found that both compounds inhibited NF-κB transcriptional activity, induced mitochondrial membrane potential depolarization and increased the percentage of reactive oxygen species in the treated cancer cells in a dose-dependent manner as well. Since the anticancer effect of psiadin on cancer cells was higher than that produced by plectranthone, only psiadin was tested to determine its possible targets. The results suggested a high degree of specificity of action affecting particular cellular processes in both cancer cells. In conclusion, both terpenes, in particular psiadin, showed significant discriminative therapeutic potential between cancer and normal cells, a value that is missing in current chemotherapies.

scholarly journals Abyssinone V-4′ Methyl Ether, a Flavanone Isolated from Erythrina droogmansiana, Exhibits Cytotoxic Effects on Human Breast Cancer Cells by Induction of Apoptosis and Suppression of Invasion

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Stéphane Zingue ◽  
Abel Joël Gbaweng Yaya ◽  
Julia Cisilotto ◽  
Larissa Vanelle Kenmogne ◽  
Emmanuel Talla ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Cell Lines ◽  
Methyl Ether ◽  
Breast Cancer Cells ◽  
Molecular Mechanisms ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Cytotoxic Effects

Abyssinone V-4′ methyl ether (AVME) isolated from Erythrina droogmansiana was recently reported to exhibit anti-mammary tumor effect in mice. The present work was therefore aimed at elucidating its cellular and molecular mechanisms. To achieve our goal, the cytotoxicity of AVME against tumoral and non-tumoral cell lines was evaluated by resazurin reduction test; flow cytometry allowed us to evaluate the cell cycle and mechanisms of cell death; the mitochondrial transmembrane potential, reactive oxygen species (ROS) levels, and caspase activities as well as apoptosis-regulatory proteins (Bcl-2 and Bcl-XL) were measured in MDA-MB-231 cells. Further, the antimetastatic potential of AVME was evaluated by invasion assay. AVME exhibited cytotoxic effects in all tested tumor cell lines and induced a significant increase in the percentage of MDA-MB-231 cells at G2/M and S phases of the cell cycle in a concentration-dependent manner. AVME also induced apoptosis in MDA-MB-231 cells, which was accompanied by the activation of caspase-3 and caspase-9 and downregulation of Bcl-2 and Bcl-XL proteins. Moreover, AVME suppressed cancer cell invasion by the inhibition of the metalloproteinase-9 activity. Findings from this study suggest that AVME has anti-breast cancer activities expressed through mitochondrial proapoptotic pathway including impairment of aggressive behaviors of breast cancer cells.

scholarly journals Metformin Promotes Anti-tumor Biomarkers in Human Endometrial Cancer Cells

2020 ◽  
Vol 27 (1) ◽  
pp. 267-277 ◽  
Author(s):  
John Mark P Pabona ◽  
Alexander F Burnett ◽  
Dustin M Brown ◽  
Charles M Quick ◽  
Frank A Simmen ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cancer Cells ◽  
Receptor Expression ◽  
Tumor Biomarker ◽  
Mrna Levels ◽  
Multiple Cancer ◽  
Preventative Strategy ◽  
Patients With Diabetes ◽  
Ec Cells ◽  
Cancer Types

AbstractMetformin (MET) is increasingly implicated in reducing the incidence of multiple cancer types in patients with diabetes. However, similar effects of MET in non-diabetic women with endometrial cancer (EC) remain unknown. In a pilot study, obese non-diabetic women diagnosed with type 1, grade 1/2 EC, and consenting to participate were randomly assigned to receive MET or no MET (control (CON)) during the pre-surgical window between diagnosis and hysterectomy. Endometrial tumors obtained at surgery (MET, n = 4; CON, n = 4) were analyzed for proliferation (Ki67), apoptosis (TUNEL), and nuclear expression of ERα, PGR, PTEN, and KLF9 proteins in tumor glandular epithelial (GE) and stromal (ST) cells. The percentages of immunopositive cells for PGR and for KLF9 in GE and for PTEN in ST were higher while those for ERα in GE but not ST were lower, in tumors of MET vs. CON patients. The numbers of Ki67- and TUNEL-positive cells in tumor GE and ST did not differ between groups. In human Ishikawa endometrial cancer cells, MET treatment (60 μM) decreased cell numbers and elicited distinct temporal changes in ESR1, KLF9, PGR, PGR-B, KLF4, DKK1, and other tumor biomarker mRNA levels. In the context of reduced KLF9 expression (by siRNA targeting), MET rapidly amplified PGR, PGR-B, and KLF4 transcript levels. Our findings suggest that MET acts directly in EC cells to modify steroid receptor expression and signaling network and may constitute a preventative strategy against EC in high-risk non-diabetic women.

scholarly journals Tamoxifen Represses miR-200 MicroRNAs and Promotes Epithelial-to-Mesenchymal Transition by Up-Regulating c-Myc in Endometrial Carcinoma Cell Lines

Endocrinology ◽  
2013 ◽  
Vol 154 (2) ◽  
pp. 635-645 ◽  
Author(s):  
Jiu-Xu Bai ◽  
Bo Yan ◽  
Zhi-Ning Zhao ◽  
Xiao Xiao ◽  
Wei-Wei Qin ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Endometrial Carcinoma ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Molecular Mechanisms ◽  
Cancer Cell Lines ◽  
Endometrial Cancer Cell ◽  
Mesenchymal Transition ◽  
Wide Range

Although tamoxifen (TAM), a selective estrogen receptor modulator, has been widely used in the treatment of hormone-responsive breast cancer, its estrogen-like effect increases the risk of endometrial cancer. However, the molecular mechanisms of TAM-induced endometrial carcinoma still remain unclear. In this report, we explored the role of microRNAs (miRNAs) in TAM-induced epithelial-mesenchymal transition (EMT) in ECC-1 and Ishikawa endometrial cancer cell lines and found miR-200 is involved in this process via the regulation of c-Myc. When treated with TAM, ECC-1 and Ishikawa cells were characterized by higher invasiveness and motility and underwent EMT. miR-200, a miRNA family with tumor suppressive functions in a wide range of cancers, was found reduced in response to TAM treatment. Consistent with zinc finger E-box binding homeobox 2, which was confirmed as a direct target of miR-200b in endometrial cancer cell lines, some other key factors of EMT such as Snail and N-cadherin increased, whereas E-cadherin decreased in the TAM-treated cells, contributing to TAM-induced EMT in these endometrial cancer cells. In addition, we showed that c-Myc directly binds to and represses the promoter of miR-200 miRNAs, and its up-regulation in TAM-treated endometrial cancer cells leads to the down-regulation of miR-200 and eventually to EMT. Collectively, our data suggest that TAM can repress the miR-200 family and induce EMT via the up-regulation of c-Myc in endometrial cancer cells. These findings describe a possible mechanism of TAM-induced EMT in endometrial cancer and provide a potential new therapeutic strategy for it.

scholarly journals Anticancer Potential of Biogenic Silver Nanoparticles: A Mechanistic Study

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 707
Author(s):  
Mohd Shahnawaz Khan ◽  
Alya Alomari ◽  
Shams Tabrez ◽  
Iftekhar Hassan ◽  
Rizwan Wahab ◽  
...  
Keyword(s):  
Silver Nanoparticles ◽  
Cancer Cells ◽  
Cell Lines ◽  
Human Life ◽  
Mechanistic Study ◽  
Dependent Manner ◽  
Rt Pcr ◽  
Cell Viability Assay ◽  
Hct 116 ◽  
Mcf 7

The continuous loss of human life due to the paucity of effective drugs against different forms of cancer demands a better/noble therapeutic approach. One possible way could be the use of nanostructures-based treatment methods. In the current piece of work, we have synthesized silver nanoparticles (AgNPs) using plant (Heliotropiumbacciferum) extract using AgNO3 as starting materials. The size, shape, and structure of synthesized AgNPs were confirmed by various spectroscopy and microscopic techniques. The average size of biosynthesized AgNPs was found to be in the range of 15 nm. The anticancer potential of these AgNPs was evaluated by a battery of tests such as MTT, scratch, and comet assays in breast (MCF-7) and colorectal (HCT-116) cancer models. The toxicity of AgNPs towards cancer cells was confirmed by the expression pattern of apoptotic (p53, Bax, caspase-3) and antiapoptotic (BCl-2) genes by RT-PCR. The cell viability assay showed an IC50 value of 5.44 and 9.54 µg/mL for AgNPs in MCF-7 and HCT-116 cell lines respectively. We also observed cell migration inhibiting potential of AgNPs in a concentration-dependent manner in MCF-7 cell lines. A tremendous rise (150–250%) in the production of ROS was observed as a result of AgNPs treatment compared with control. Moreover, the RT-PCR results indicated the difference in expression levels of pro/antiapoptotic proteins in both cancer cells. All these results indicate that cell death observed by us is mediated by ROS production, which might have altered the cellular redox status. Collectively, we report the antimetastasis potential of biogenic synthesized AgNPs against breast and colorectal cancers. The biogenic synthesis of AgNPs seems to be a promising anticancer therapy with greater efficacy against the studied cell lines.

scholarly journals Drug-Like Small Molecule HSP27 Functional Inhibitor Sensitizes Lung Cancer Cells to Gefitinib or Cisplatin by Inducing Altered Cross-Linked Hsp27 Dimers

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 630
Author(s):  
Hawon Yoo ◽  
Seul-Ki Choi ◽  
Jaeok Lee ◽  
So Hyeon Park ◽  
You Na Park ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Cell Lines ◽  
Small Molecule ◽  
Anticancer Agents ◽  
Tumor Growth Inhibition ◽  
Dependent Manner ◽  
Hsp27 Expression ◽  
Cancer Aggressiveness

Relationships between heat shock protein 27 (HSP27) and cancer aggressiveness, metastasis, drug resistance, and poor patient outcomes in various cancer types including non-small cell lung cancer (NSCLC) were reported, and inhibition of HSP27 expression is suggested to be a possible strategy for cancer therapy. Unlike HSP90 or HSP70, HSP27 does not have an ATP-binding pocket, and no effective HSP27 inhibitors have been identified. Previously, NSCLC cancer cells were sensitized to radiation and chemotherapy when co-treated with small molecule HSP27 functional inhibitors such as zerumbone (ZER), SW15, and J2 that can induce abnormal cross-linked HSP27 dimer. In this study, cancer inhibition effects of NA49, a chromenone compound with better solubility, longer circulation time, and less toxicity than J2, were examined in combination with anticancer drugs such as cisplatin and gefitinib in NSCLC cell lines. When the cytotoxic drug cisplatin was treated in combination with NA49 in epidermal growth factor receptors (EGFRs) WT cell lines, sensitization was induced in an HSP27 expression-dependent manner. With gefitinib treatment, NA49 showed increased combination effects in both EGFR WT and Mut cell lines, also with HSP27 expression-dependent patterns. Moreover, NA49 induced sensitization in EGFR Mut cells with a secondary mutation of T790M when combined with gefitinib. Augmented tumor growth inhibition was shown with the combination of cisplatin or gefitinib and NA49 in nude mouse xenograft models. These results suggest the combination of HSP27 inhibitor NA49 and anticancer agents as a candidate for overcoming HSP27-mediated drug resistance in NSCLC patients.

Stimulation of the acute-phase response in simian virus 40-hepatocyte cell lines

1989 ◽  
Vol 9 (7) ◽  
pp. 2779-2786
Author(s):  
W S Liao ◽  
K T Ma ◽  
C D Woodworth ◽  
L Mengel ◽  
H C Isom
Keyword(s):  
Cell Lines ◽  
Acute Phase ◽  
Molecular Mechanisms ◽  
Constitutive Expression ◽  
Simian Virus 40 ◽  
Normal Liver ◽  
Simian Virus ◽  
Cdna Clones ◽  
Dependent Manner ◽  
Amyloid A

Seven simian virus 40 (SV40)-hepatocyte cell lines were characterized with respect to the ability to express eight liver acute-phase genes. cDNA clones corresponding to albumin, serum amyloid A, alpha 1-acid glycoprotein, haptoglobin, alpha-, beta-, and gamma-fibrinogen, and alpha 1-major-acute-phase protein mRNAs were used in Northern (RNA) or slot blot analyses. In the noninduced state, six of the seven cell lines showed significant (i.e., liverlike) levels of constitutive expression of all genes examined except that expression of haptoglobin mRNA was considerable lower than in the normal liver. To examine whether these immortalized liver cells can respond appropriately to inflammatory mediators, cells were treated with conditioned medium from activated human monocytes or mixed lymphocyte cultures. Results showed that these SV40-hepatocyte cell lines responded to the conditioned media in culture by down-regulating albumin gene expression and up-regulating other acute-phase genes in a time- and dose-dependent manner. These results indicate that the SV40-hepatocytes retained not only the ability to express a number of acute-phase genes but also the ability to respond to external stimuli. The usefulness of these cell lines for analysis of the molecular mechanisms involved in the regulation of these acute-phase genes is discussed.

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