scholarly journals Structural and Functional Analyses of Human ChaC2 in Glutathione Metabolism

Biomolecules ◽  
2019 ◽  
Vol 10 (1) ◽  
pp. 31 ◽  
Author(s):  
Yen T. K. Nguyen ◽  
Joon Sung Park ◽  
Jun Young Jang ◽  
Kyung Rok Kim ◽  
Tam T. L. Vo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Catalytic Mechanism ◽  
Docking Study ◽  
Binding Mode ◽  
Structural Features ◽  
Glutathione Metabolism ◽  
Binding Assays ◽  
Biochemical Analyses ◽  
Functional Analyses

Glutathione (GSH) degradation plays an essential role in GSH homeostasis, which regulates cell survival, especially in cancer cells. Among human GSH degradation enzymes, the ChaC2 enzyme acts on GSH to form 5-l-oxoproline and Cys-Gly specifically in the cytosol. Here, we report the crystal structures of ChaC2 in two different conformations and compare the structural features with other known γ-glutamylcyclotransferase enzymes. The unique flexible loop of ChaC2 seems to function as a gate to achieve specificity for GSH binding and regulate the constant GSH degradation rate. Structural and biochemical analyses of ChaC2 revealed that Glu74 and Glu83 play crucial roles in directing the conformation of the enzyme and in modulating the enzyme activity. Based on a docking study of GSH to ChaC2 and binding assays, we propose a substrate-binding mode and catalytic mechanism. We also found that overexpression of ChaC2, but not mutants that inhibit activity of ChaC2, significantly promoted breast cancer cell proliferation, suggesting that the GSH degradation by ChaC2 affects the growth of breast cancer cells. Our structural and functional analyses of ChaC2 will contribute to the development of inhibitors for the ChaC family, which could effectively regulate the progression of GSH degradation-related cancers.

scholarly journals Dermatan Sulfate Affects Breast Cancer Cell Function via the Induction of Necroptosis

Cells ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 173
Author(s):  
Grzegorz Wisowski ◽  
Adam Pudełko ◽  
Krystyna Olczyk ◽  
Monika Paul-Samojedny ◽  
Ewa M. Koźma
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cell Function ◽  
Dermatan Sulfate ◽  
Variable Structure ◽  
Structural Features ◽  
Luminal Breast Cancer ◽  
Binding Properties

Dermatan sulfate (DS) is widespread in the extracellular matrix (ECM) of animal tissues. This glycosaminoglycan is characterized by a variable structure, which is reflected in the heterogeneity of its sulfation pattern. The sulfate groups are responsible for the binding properties of DS, which determine an interaction profile of this glycan. However, the detailed role of DS in biological processes such as the neoplasm is still poorly understood. The aim of the study was to assess the effects of the structural variants of DS on breast cancer cells. We found that DS isoforms from normal and fibrotic fascia as well as from intestinal mucosa were able to quickly induce oxidative stress in the cytoplasm and affect the mitochondrial function in luminal breast cancer cells. Moreover, the variants caused the necroptosis of the cells most likely via the first of these mechanisms. This death was responsible for a reduction in the viability and number of breast cancer cells. However, the dynamics and intensity of all of the DS variants-triggered effects were strongly dependent on the cell type and the structure of these molecules. The most pronounced activity was demonstrated by those variants that shared structural features with the DS from the tumor niche.

scholarly journals Phosphoinositide 3-kinase signaling pathway mediated by p110α regulates invadopodia formation

2011 ◽  
Vol 193 (7) ◽  
pp. 1275-1288 ◽  
Author(s):  
Hideki Yamaguchi ◽  
Shuhei Yoshida ◽  
Emi Muroi ◽  
Nachi Yoshida ◽  
Masahiro Kawamura ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Pi3k Signaling ◽  
Gelatin Matrix ◽  
Downstream Effectors ◽  
Extracellular Stimuli ◽  
Phosphoinositide 3 Kinase ◽  
Functional Analyses ◽  
Invadopodia Formation

Invadopodia are extracellular matrix–degrading protrusions formed by invasive cancer cells that are thought to function in cancer invasion. Although many invadopodia components have been identified, signaling pathways that link extracellular stimuli to invadopodia formation remain largely unknown. We investigate the role of phosphoinositide 3-kinase (PI3K) signaling during invadopodia formation. We find that in human breast cancer cells, both invadopodia formation and degradation of a gelatin matrix were blocked by treatment with PI3K inhibitors or sequestration of D-3 phosphoinositides. Functional analyses revealed that among the PI3K family proteins, the class I PI3K catalytic subunit p110α, a frequently mutated gene product in human cancers, was selectively involved in invadopodia formation. The expression of p110α with cancerous mutations promoted invadopodia-mediated invasive activity. Furthermore, knockdown or inhibition of PDK1 and Akt, downstream effectors of PI3K signaling, suppressed invadopodia formation induced by p110α mutants. These data suggest that PI3K signaling via p110α regulates invadopodia-mediated invasion of breast cancer cells.

In vitro cytotoxicity of Clinacanthus nutans fractions on breast cancer cells and molecular docking study of sulphur containing compounds against caspase-3

2020 ◽  
Vol 135 ◽  
pp. 110869 ◽  
Author(s):  
Roziasyahira Mutazah ◽  
Hazrulrizawati Abd Hamid ◽  
Aizi Nor Mazila Ramli ◽  
Mohd Fadhlizil Fasihi Mohd Aluwi ◽  
Mashitah M. Yusoff
Keyword(s):  
Breast Cancer ◽  
Molecular Docking ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Caspase 3 ◽  
Docking Study ◽  
In Vitro Cytotoxicity ◽  
Molecular Docking Study ◽  
Clinacanthus Nutans

scholarly journals The conformation of the estrogen receptor directs estrogen-induced apoptosis in breast cancer: a hypothesis

2011 ◽  
Vol 5 (1) ◽  
Author(s):  
Philipp Maximov ◽  
Surojeet Sengupta ◽  
Joan S. Lewis-Wambi ◽  
Helen R. Kim ◽  
Ramona F. Curpan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Binding Mode ◽  
Type I ◽  
Mcf7 Cells ◽  
Protein Levels ◽  
Induced Apoptosis

Abstract: Estrogens are classified as type I (planar) and type II (angular) based on their structures. In this study, we used triphenylethylenes (TPEs) compounds related to 4-hydroxytamoxifen 4OHT to address the hypothesis that the conformation of the liganded estrogen receptor (ERα) can dictate the E2-induced apoptosis of the ER+ breast cancer cells.: ERα positive MCF7:5C cells were used to study apoptosis induced by E2, 4OHT and TPEs. Growth and apoptosis assays were used to evaluate apoptosis and the ability to reverse E2-induced apoptosis. ERα protein was measured by Western blotting to investigate the destruction of ERα by TPEs in MCF7 cells. Chromatin immunoprecipitation (ChIP) assays were performed to study the in vivo recruitment of ERα and SRC3 at classical E2-responsive promoter TFF1 (PS2) by TPEs. Molecular modeling was used to predict the binding mode of the TPE to the ERα.: TPEs were not only unable to induce efficient apoptosis in MCF7:5C cells but also reversed the E2-induced apoptosis similar to 4OHT. Furthermore, the TPEs and 4OHT did not reduce the ERα protein levels unlike E2. ChIP assay confirmed very weak recruitment of SRC3 despite modest recruitment of ERα in the presence of TPEs. Mole-ular modeling suggests that TPE would bind in antagonistic mode with ERα.: Our results advances the hypothesis that the TPE liganded ERα complex structurally resembles the 4OHT bound ERα and cannot efficiently recruit co-activator SRC3. As a result, the TPE complex cannot induce apoptosis of ER+ breast cancer cells, although it can cause growth of the breast cancer cells. The conformation of the estrogen-ER complex differentially controls growth and apoptosis.

Alkylamino Phenol Derivative Induces Apoptosis by Inhibiting EGFR Signaling Pathway in Breast Cancer Cells

2020 ◽  
Vol 20 (7) ◽  
pp. 809-819 ◽  
Author(s):  
Suresh Palanivel ◽  
Olli Yli-Harja ◽  
Meenakshisundaram Kandhavelu
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Breast Cancer Cells ◽  
Growth Factor Receptor ◽  
Annexin V ◽  
Binding Mode ◽  
Quantitative Structure Activity Relationship ◽  
Phenol Derivative ◽  
Egfr Signaling Pathway

Background and Objective: The present study was carried out to evaluate the anticancer property of an alkylamino phenol derivative -2-((3,4-Dihydroquinolin-1(2H)-yl)(p-tolyl)methyl)phenol) (THTMP) against human breast cancer cells. The cytotoxicity of the THTMP was assessed to know its specificity towards breast cancer cells without affecting the normal cells. Methods: The THTMP was synthesized and the cytotoxicity was assessed by MTT assay, Caspases enzyme activity, DNA fragmentation and FITC/Annexin V, AO/EtBr staining, RT-PCR and QSAR. In addition, ADME analysis was executed to understand the mode of action of THTMP. Results: THTMP showed potential cytotoxic activity against the growth of MCF7 and SK-BR3 cells with the IC50 values of 87.92μM and 172.51μM, respectively. Interestingly, THTMP found to activate caspase 3 and caspase 9 enzymes in cancer cells, which are the key enzymes implicated in apoptosis. THTMP induced apoptosis in which 33% of the cells entered the late apoptotic stage after 24h of treatment. The results also revealed that the apoptotic response could be influenced by the association of THTMP with the Epidermal Growth Factor Receptor (EGFR) mediated inhibition of the Phosphatidylinositol 3-Kinase (PI3K)/S6K1 signaling pathway. In addition, docking was performed to study the binding mode of the THTMP, which shows better interaction with EGFR. The structural elucidation of THTMP by Quantitative Structure-Activity Relationship model (QSAR) and ADMET screening suggested, THTMP as an effective anticancer compound. Conclusion: This work strengthens the potential of a promising drug-like compound, THTMP, for the discovery of anticancer drug against breast cancer.

scholarly journals MiR-200c Sensitizes Breast Cancer Cells to Carboplatin Treatment by Decreasing MDR1 Expression

2021 ◽  
Author(s):  
Shiva Najjary ◽  
Sahar Safaee ◽  
Ahad Mokhtarzadeh ◽  
Mohammad Amini ◽  
Nadia Bolandi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
High Rate ◽  
Expression Level ◽  
Mcf7 Cells ◽  
Mdr1 Gene Expression ◽  
Mdr1 Expression ◽  
Functional Analyses ◽  
Resistance To Chemotherapy

Abstract Background: Breast cancer (BC) is one of the most common cancers worldwide and is associated with a high rate of cancer mortality in women. Resistance to chemotherapy is considered a significant problem and a major challenge for the treatment of patients with BC. miR-200c belongs to a family of miRNAs that act as tumor inhibitors. The expression level of miR-200c has been reported to be decreased in cancers, especially in BC. The increased miR-200c expression can be considered as a potent inhibitor of drug resistance and tumor progression. Methods and Results: The current study examined the effect of miR-200c on enhancing the BC cells' sensitivity to Carboplatin through targeting MDR1 expression. To perform functional analyses, mimic miR-200c transfected to MCF7 cells. Then, the viability of the cells was investigated via MTT assay. Finally, the expression of associated genes assessed using qRT-PCR. The results indicated that downregulation of miR-200c was occurred in MCF7 cells in comparison to control. Besides, restoring miR-200c expression by regulating the expression level of the apoptotic gene reduces the viability of cancer cells. Moreover, miR-200c increased the sensitivity of MCF7 cells to Carboplatin via reducing the MDR1 gene expression. Conclusions: This study provided valuable data showing that miR-200c enhances the effect of carboplatin as a clinically approved chemotherapeutic agent, and restoring its expression could be considered as a promising targeted adjuvant therapy for BC management.

scholarly journals Co-Inhibition of P-gp and Hsp90 by an Isatin-Derived Compound Contributes to the Increase of the Chemosensitivity of MCF7/ADR-Resistant Cells to Doxorubicin

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 90
Author(s):  
Ashraf N. Abdalla ◽  
Miriana Di Stefano ◽  
Giulio Poli ◽  
Tiziano Tuccinardi ◽  
Ammar Bader ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Molecular Modeling ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Efflux Pump ◽  
Binding Mode ◽  
Inhibitory Effect ◽  
In Vivo Studies ◽  
Mcf7 Cells

Breast cancer is a complex and multi-drug resistant (MDR) disease, which could result in the failure of many chemotherapeutic clinical agents. Discovering effective molecules from natural products or by derivatization from known compounds is the interest of many research studies. The first objective of the present study is to investigate the cytotoxic combinatorial, chemosensitizing, and apoptotic effects of an isatin derived compound (5,5-diphenylimidazolidine-2,4-dione conjugated with 5-substituted isatin, named HAA2021 in the present study) against breast cancer cells (MCF7) and breast cancer cells resistant to doxorubicin (MCF7/ADR) when combined with doxorubicin. The second objective is to investigate the binding mode of HAA2021 withP-glycoprotein (P-gp) and heat shock protein 90 (Hsp90), and to determine whether their co-inhibition by HAA2021 contribute to the increase of the chemosensitization of MCF7/ADR cells to doxorubicin. The combination of HAA2021, at non-toxic doses, with doxorubicin synergistically inhibited the proliferation while inducing significant apoptosis in MCF7 cells. Moreover, HAA2021 increased the chemosensitization of MCF7/ADR cells to doxorubicin, resulting in increased cytotoxicity/selectivity and apoptosis-inducing efficiency compared with the effect of doxorubicin or HAA2021 alone against MCF7/ADR cells. Molecular modeling showed that two molecules of HAA2021 bind to P-gp at the same time, causing P-gp inhibitory effect of the MDR efflux pump, and accumulation of Rhodamine-123 (Rho123) in MCF7/ADR cells. Furthermore, HAA2021 stably interacted with Hsp90α more efficiently compared with 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), which was confirmed with the surface plasmon resonance (SPR) and molecular modeling studies. Additionally, HAA2021 showed multi-target effects via the inhibition of Hsp90 and nuclear factor kappa B (NF-𝜅B) proteins in MCF7 and MCF7/ADR cells. Results of real time-PCR also confirmed the synergistic co-inhibition of P-gp/Hsp90α genes in MCF7/ADR cells. Further pharmacokinetic and in vivo studies are warranted for HAA2021 to confirm its anticancer capabilities.

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