scholarly journals Identification of a Unique Core Domain of Par-4 Sufficient for Selective Apoptosis Induction in Cancer Cells

2003 ◽  
Vol 23 (16) ◽  
pp. 5516-5525 ◽  
Author(s):  
Nadia El-Guendy ◽  
Yanming Zhao ◽  
Sushma Gurumurthy ◽  
Ravshan Burikhanov ◽  
Vivek M. Rangnekar
Keyword(s):  
Cancer Cells ◽  
Leucine Zipper ◽  
Function Analysis ◽  
Molecular Therapy ◽  
Target Range ◽  
Nuclear Localization Sequence ◽  
Apoptosis Induction ◽  
Normal Cells ◽  
Core Domain ◽  
Leucine Zipper Domain

ABSTRACT Recent studies indicated that the leucine zipper domain protein Par-4 induces apoptosis in certain cancer cells by activation of the Fas prodeath pathway and coparallel inhibition of NF-κB transcriptional activity. However, the intracellular localization or functional domains of Par-4 involved in apoptosis remained unknown. In the present study, structure-function analysis indicated that inhibition of NF-κB activity and apoptosis is dependent on Par-4 translocation to the nucleus via a bipartite nuclear localization sequence, NLS2. Cancer cells that were resistant to Par-4-induced apoptosis retained Par-4 in the cytoplasm. Interestingly, a 59-amino-acid core that included NLS2 but not the C-terminal leucine zipper domain was necessary and sufficient to induce Fas pathway activation, inhibition of NF-κB activity, and apoptosis. Most important, this core domain had an expanded target range for induction of apoptosis, extending to previously resistant cancer cells but not to normal cells. These findings have identified a unique death-inducing domain selective for apoptosis induction in cancer cells (SAC domain) which holds promise for identifying key differences between cancer and normal cells and for molecular therapy of cancer.

scholarly journals The Effect of Plasma Activated Medium and PBS on Human Melanoma Cells Compared With Other Cancer and Normal Cells

2021 ◽  
Author(s):  
Dominika Sersenová ◽  
Zdenko Machala ◽  
Vanda Repiská ◽  
Helena Gbelcová
Keyword(s):  
Cancer Cells ◽  
Treatment Time ◽  
Ambient Air ◽  
Melanoma Cells ◽  
Clinical Applications ◽  
Dermal Fibroblasts ◽  
Apoptosis Induction ◽  
Normal Cells ◽  
Anticancer Effects ◽  
Cold Plasmas

Plasma medicine is a new field focusing on biomedical and clinical applications of cold physical plasmas, including their anticancer effects. Cold plasmas can be applied directly or indirectly as plasma activated liquids (PAL). The effect of plasma activated cell growth medium (PAM) and plasma activated phosphate buffered saline (PAPBS) were tested using a plasma pen generating streamer corona discharge in ambient air, on different cancer cell lines (melanoma A375, glioblastoma LN229 and pancreatic cancer MiaPaCa-2) and normal cells (human dermal fibroblasts HDFa). The viability reduction and apoptosis induction were detected in all cancer cells after incubation in PAL. In melanoma cells we focused on detailed insights to the apoptotic pathways. The anticancer effects depend on the plasma treatment time or PAL concentration. The first 30 minutes of incubation in PAL were enough to start processes leading to the cell death. In fibroblasts, no apoptosis induction was observed, only PAPBS, activated for longer time, slightly decreased their viability. Anticancer effects of PAM and PAPBS on cancer cells showed selectivity compared to normal fibroblasts, depended on correctly chosen activation time and PAL concentration. This selectivity, supported by optimum ratio of hydrogen peroxide and nitrites in PAL, is very promising for potential clinical applications.

scholarly journals Titania Nanosheets Generates Peroxynitrite for S-Nitrosylation and Enhanced p53 Function in Lung Cancer Cells

2021 ◽  
Author(s):  
Rapeepun Soonnarong ◽  
Sucharat Tungsukruthai ◽  
Bodee Nutho ◽  
Thanyada Rungrotmongkol ◽  
Chanida Vinayanuwattikun ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Lung Cancer ◽  
Molecular Dynamics ◽  
Cancer Therapy ◽  
Cancer Cells ◽  
Mechanism Of Action ◽  
Lung Cancer Cells ◽  
Positive Staining ◽  
Apoptosis Induction ◽  
Normal Cells

Abstract Background: Metal oxide nanomaterials are increasingly being exploited in cancer therapy thanks to their unique properties, which can enhance the efficacy of current cancer therapies. However, the nanotoxicity and mechanism of Ti0.8O2 nanosheets for specific site-targeting strategies in NSCLC have not yet been investigated.Methods: The effects of Ti0.8O2 nanosheets on cytotoxicity in NSCLC cells and normal cells were examined. The apoptosis characteristics, including condensed and fragmented nuclei, as assessed by positive staining with annexin V. The cellular uptake of the nanosheets and the induction of stress fiber were assessed via transmission electron microscopy (TEM) and scanning electron microscopy (SEM) analyses, respectively. We also evaluated the expression of protein in death mechanism to identify the molecular mechanisms behind the toxicity of these cells. We investigated the relationship between S-nitrosylation and the increase in p53 stability by molecular dynamics.Results: Ti0.8O2 nanosheets caused cytotoxicity in several lung cancer cells, but not in normal cells. The nanosheets could enter lung cancer cells and exert an apoptosis induction. Results for protein analysis further indicated the activation of p53, increased Bax, decreased Bcl-2 and Mcl-1, and activation of caspase-3. The nanosheets also exhibited a substantial apoptosis effect in drug-resistant metastatic primary lung cancer cells, and it was found that the potency of the nanosheets was dramatically higher than that of cisplatin and etoposide. In terms of their mechanism of action, we found that the mode of apoptosis induction was through the generation of cellular ONOO− mediated the S-nitrosylation of p53 at C182. Molecular dynamics analysis further showed that the S-nitrosylation of one C182 stabilized the p53 dimer. Consequently, this nitrosylation of the protein led to an upregulation of p53 through its stabilization.Conclusions: Taking all the evidence together, we provided information on the apoptosis induction effect of the nanosheets through a molecular mechanism involving reactive nitrogen species, which affects the protein stability; thus emphasizing the novel mechanism of action of nanomaterials for cancer therapy.

Molecular Studies on Novel Antitumor Bis 1,4-Dihydropyridine Derivatives Against Lung Carcinoma and their Limited Side Effects on Normal Melanocytes

2019 ◽  
Vol 18 (15) ◽  
pp. 2156-2168 ◽  
Author(s):  
Magda F. Mohamed ◽  
Nada S. Ibrahim ◽  
Ahmed H.M. Elwahy ◽  
Ismail A. Abdelhamid
Keyword(s):  
Breast Cancer ◽  
Side Effects ◽  
Cancer Cells ◽  
Cell Line ◽  
Lung Carcinoma ◽  
Carcinoma Cell ◽  
Normal Cells ◽  
Lung Carcinoma Cell Line ◽  
Molecular Studies ◽  
Dihydropyridine Derivatives

Background: Cancer is a complex genetic disease which is characterized by an abnormal cell growth, invasion and spreading to other parts of the body. There are several factors that lead to cancer by causing DNA damage and the impairment of its repair. Treatment of cancer using the chemotherapeutic drugs have adverse side effects such as toxicity as they lose their specificity toward cancer cells and affect also normal cells. Moreover, the cancer cells can resist the chemotherapeutic agents and make them ineffective. For these reasons, much attentions have been paid to develop new drugs with limited side effects on normal cells and to diminish cancer resistance to drug chemotherapy. Recently, some 1,4-dihydropyridine derivatives were reported to act as Multi-Drug Resistance (MDR) modulators that inhibit p-glycoprotein which is responsible for the inability of drugs to enter the cancer cells. Also 1,4-DHPs have antimutagenic properties against chemicals via modulating DNA repair when studied on drosophila. Objective: The objective of this study is the synthesis of bis 1,4-DHPs incorporating ester as well as ether linkages and evaluate the anticancer activity of new compounds for synergistic purpose. Different genetic tools were used in an attempt to know the mechanism of action of this compound against lung cancer. Method: An efficient one pot synthesis of bis 1,4-DHPs using 3-aminocrotononitrile and bis(aldehydes) has been developed. The cytotoxic effect against human cell lines MCF7, and A549 cell lines was evaluated. Results: All compounds exhibited better cytotoxicity toward lung carcinoma cells than breast cancer cells. With respect to lung carcinoma cell line (A549), compound 10 was the most active compound and the three other compounds 7, 8, and 9 showed comparable IC50 values. In case of breast cancer cell line (MCF7), the most active one was compound 7, while compound 8 recorded the least activity. Conclusion: we have developed an efficient method for the synthesis of novel bis 1,4-dihydropyridine derivatives incorporating ester or ether linkage. All compounds showed better cytotoxicity results against A549 than MCF7, so that lung carcinoma cell line was chosen to perform the molecular studies on it. The results showed that all compounds (7, 8, 9 and 10) caused cell cycle arrest at G1 phase. The molecular docking study on CDK2 confirmed the results of cell cycle assay which showed good binding energy between the compounds and the active site of enzyme indicating the inhibition of the enzyme.

Elucidation of the Chemopreventive Role of Stigmasterol Against Jab1 in Gall Bladder Carcinoma

2019 ◽  
Vol 19 (6) ◽  
pp. 826-837 ◽  
Author(s):  
Pratibha Pandey ◽  
Preeti Bajpai ◽  
Mohammad H. Siddiqui ◽  
Uzma Sayyed ◽  
Rohit Tiwari ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bladder Cancer ◽  
Gall Bladder ◽  
Cancer Cells ◽  
Caspase 3 ◽  
Annexin V ◽  
Gall Bladder Cancer ◽  
Apoptosis Induction ◽  
Bladder Cancer Cells ◽  
Hoechst Staining

Background:Plant sterols have proven a potent anti-proliferative and apoptosis inducing agent against several carcinomas including breast and prostate cancers. Jab1 has been reported to be involved in the progression of numerous carcinomas. However, antiproliferative effects of sterols against Jab1 in gall bladder cancer have not been explored yet.Objective:In the current study, we elucidated the mechanism of action of stigmasterol regarding apoptosis induction mediated via downregulation of Jab1 protein in human gall bladder cancer cells.Methods:In our study, we performed MTT and Trypan blue assay to assess the effect of stigmasterol on cell proliferation. In addition, RT-PCR and western blotting were performed to identify the effect of stigmasterol on Jab1 and p27 expression in human gall bladder cancer cells. We further performed cell cycle, Caspase-3, Hoechst and FITC-Annexin V analysis, to confirm the apoptosis induction in stigmasterol treated human gall bladder cancer cells.Results:Our results clearly indicated that stigmasterol has up-regulated the p27 expression and down-regulated Jab1 gene. These modulations of genes might occur via mitochondrial apoptosis signaling pathway. Caspase-3 gets activated with the apoptotic induction. Increase in apoptotic cells and DNA were confirmed through annexin V staining, Hoechst staining, and cell cycle analysis.Conclusion:Thus, these results strongly suggest that stigmasterol has the potential to be considered as an anticancerous therapeutic agent against Jab1 in gall bladder cancer.

scholarly journals Computational Methods for Structure-to-Function Analysis of Diet-Derived Catechins-Mediated Targeting of In Vitro Vasculogenic Mimicry

2021 ◽  
Vol 20 ◽  
pp. 117693512110092
Author(s):  
Abicumaran Uthamacumaran ◽  
Narjara Gonzalez Suarez ◽  
Abdoulaye Baniré Diallo ◽  
Borhane Annabi
Keyword(s):  
Machine Learning ◽  
Cancer Cells ◽  
Structural Changes ◽  
Function Analysis ◽  
Vasculogenic Mimicry ◽  
Machine Learning Algorithms ◽  
Emergent Behavior ◽  
Molecular Signature ◽  
Ovarian Cancer Cells

Background: Vasculogenic mimicry (VM) is an adaptive biological phenomenon wherein cancer cells spontaneously self-organize into 3-dimensional (3D) branching network structures. This emergent behavior is considered central in promoting an invasive, metastatic, and therapy resistance molecular signature to cancer cells. The quantitative analysis of such complex phenotypic systems could require the use of computational approaches including machine learning algorithms originating from complexity science. Procedures: In vitro 3D VM was performed with SKOV3 and ES2 ovarian cancer cells cultured on Matrigel. Diet-derived catechins disruption of VM was monitored at 24 hours with pictures taken with an inverted microscope. Three computational algorithms for complex feature extraction relevant for 3D VM, including 2D wavelet analysis, fractal dimension, and percolation clustering scores were assessed coupled with machine learning classifiers. Results: These algorithms demonstrated the structure-to-function galloyl moiety impact on VM for each of the gallated catechin tested, and shown applicable in quantifying the drug-mediated structural changes in VM processes. Conclusions: Our study provides evidence of how appropriate 3D VM compression and feature extractors coupled with classification/regression methods could be efficient to study in vitro drug-induced perturbation of complex processes. Such approaches could be exploited in the development and characterization of drugs targeting VM.

scholarly journals Normal cells repel WWOX-negative or -dysfunctional cancer cells via WWOX cell surface epitope 286-299

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Yu-An Chen ◽  
Yong-Da Sie ◽  
Tsung-Yun Liu ◽  
Hsiang-Ling Kuo ◽  
Pei-Yi Chou ◽  
...  
Keyword(s):  
Cell Surface ◽  
Cancer Cells ◽  
Room Temperature ◽  
Metastatic Cancer ◽  
Normal Cells ◽  
Tgfβ Receptor ◽  
Membrane Type ◽  
Cell Invasiveness ◽  
And Control ◽  
Metastatic Cancer Cells

AbstractMetastatic cancer cells are frequently deficient in WWOX protein or express dysfunctional WWOX (designated WWOXd). Here, we determined that functional WWOX-expressing (WWOXf) cells migrate collectively and expel the individually migrating WWOXd cells. For return, WWOXd cells induces apoptosis of WWOXf cells from a remote distance. Survival of WWOXd from the cell-to-cell encounter is due to activation of the survival IκBα/ERK/WWOX signaling. Mechanistically, cell surface epitope WWOX286-299 (repl) in WWOXf repels the invading WWOXd to undergo retrograde migration. However, when epitope WWOX7-21 (gre) is exposed, WWOXf greets WWOXd to migrate forward for merge. WWOX binds membrane type II TGFβ receptor (TβRII), and TβRII IgG-pretreated WWOXf greet WWOXd to migrate forward and merge with each other. In contrast, TβRII IgG-pretreated WWOXd loses recognition by WWOXf, and WWOXf mediates apoptosis of WWOXd. The observatons suggest that normal cells can be activated to attack metastatic cancer cells. WWOXd cells are less efficient in generating Ca2+ influx and undergo non-apoptotic explosion in response to UV irradiation in room temperature. WWOXf cells exhibit bubbling cell death and Ca2+ influx effectively caused by UV or apoptotic stress. Together, membrane WWOX/TβRII complex is needed for cell-to-cell recognition, maintaining the efficacy of Ca2+ influx, and control of cell invasiveness.

scholarly journals Quantum Dots as a Good Carriers of Unsymmetrical Bisacridines for Modulating Cellular Uptake and the Biological Response in Lung and Colon Cancer Cells

Nanomaterials ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 462 ◽  
Author(s):  
Joanna Pilch ◽  
Patrycja Kowalik ◽  
Piotr Bujak ◽  
Anna M. Nowicka ◽  
Ewa Augustin
Keyword(s):  
Quantum Dots ◽  
Cancer Cells ◽  
Cellular Uptake ◽  
Laser Scanning ◽  
Biological Response ◽  
Drug Carriers ◽  
Confocal Laser ◽  
Normal Cells ◽  
H460 Cells ◽  
Hct116 Cells

Nanotechnology-based drug delivery provides a promising area for improving the efficacy of cancer treatments. Therefore, we investigate the potential of using quantum dots (QDs) as drug carriers for antitumor unsymmetrical bisacridine derivatives (UAs) to cancer cells. We examine the influence of QD–UA hybrids on the cellular uptake, internalization (Confocal Laser Scanning Microscope), and the biological response (flow cytometry and light microscopy) in lung H460 and colon HCT116 cancer cells. We show the time-dependent cellular uptake of QD–UA hybrids, which were more efficiently retained inside the cells compared to UAs alone, especially in H460 cells, which could be due to multiple endocytosis pathways. In contrast, in HCT116 cells, the hybrids were taken up only by one endocytosis mechanism. Both UAs and their hybrids induced apoptosis in H460 and HCT116 cells (to a greater extent in H460). Cells which did not die underwent senescence more efficiently following QDs–UAs treatment, compared to UAs alone. Cellular senescence was not observed in HCT116 cells following treatment with both UAs and their hybrids. Importantly, QDgreen/red themselves did not provoke toxic responses in cancer or normal cells. In conclusion, QDs are good candidates for targeted UA delivery carriers to cancer cells while protecting normal cells from toxic drug activities.

scholarly journals The Exon Junction Complex Core Represses Cancer-Specific Mature mRNA Re-Splicing: A Potential Key Role in Terminating Splicing

2021 ◽  
Vol 22 (12) ◽  
pp. 6519
Author(s):  
Yuta Otani ◽  
Ken-ichi Fujita ◽  
Toshiki Kameyama ◽  
Akila Mayeda
Keyword(s):  
Cancer Cells ◽  
Control Factor ◽  
Exon Junction Complex ◽  
Core Component ◽  
Normal Cells ◽  
Knock Down ◽  
Exon Junction ◽  
Mature Mrna ◽  
Complex Core ◽  
Specific Mrna

Using TSG101 pre-mRNA, we previously discovered cancer-specific re-splicing of mature mRNA that generates aberrant transcripts/proteins. The fact that mRNA is aberrantly re-spliced in various cancer cells implies there must be an important mechanism to prevent deleterious re-splicing on the spliced mRNA in normal cells. We thus postulated that mRNA re-splicing is controlled by specific repressors, and we searched for repressor candidates by siRNA-based screening for mRNA re-splicing activity. We found that knock-down of EIF4A3, which is a core component of the exon junction complex (EJC), significantly promoted mRNA re-splicing. Remarkably, we could recapitulate cancer-specific mRNA re-splicing in normal cells by knock-down of any of the core EJC proteins, EIF4A3, MAGOH, or RBM8A (Y14), implicating the EJC core as the repressor of mRNA re-splicing often observed in cancer cells. We propose that the EJC core is a critical mRNA quality control factor to prevent over-splicing of mature mRNA.

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