PAK5 promotes RNA helicase DDX5 sumoylation and miRNA-10b processing in a kinase-dependent manner in breast cancer

Background: Cancer stem cells (CSC) are subpopulation within the tumor that acts a part in the initiation, progression, recurrence, resistance to drugs and metastasis of cancer. It is well known that epigenetic changes lead to tumor formation in cancer stem cells and show drug resistance. Epigenetic modulators and /or their combination with different agents have been used in cancer therapy. Objective: In our study we scope out the effects of combination of a histone deacetylases inhibitor, valproic acid (VPA), and Cu(II) complex [Cu(barb-κN)(barb-κ2N,O)(phen-κN,N’)]·H2O] on cytotoxicity/apoptosis in a stem-cell enriched population (MCF-7s) obtained from parental breast cancer cell line (MCF-7). Methods: Viability of the cells was measured by the ATP assay. Apoptosis was elucidated via the assessment of caspase-cleaved cytokeratin 18 (M30 ELISA) and a group of flow cytometry analysis (caspase 3/7 activity, phosphatidylserine translocation by annexin V-FITC assay, DNA damage and oxidative stress) and 2ˈ,7ˈ–dichlorofluorescein diacetate staining. Results: The VPA combined with Cu(II) complex showed anti proliferative activity on MCF-7s cells in a dose- and time-dependently. Treatment with combination of 2.5 mM VPA and 3.12 μM Cu(II) complex induces oxidative stress in a time-dependent manner, as well as apoptosis that is evidenced by the increase in caspase 3/7 activity, positive annexin-V-FITC, and increase in M30 levels. Conclusion: The results suggest that the combination therapy induces apoptosis following increased oxidative stress, thereby making it a possible promising therapeutic strategy that further analysis is required.

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Design, Synthesis and Cytotoxicity Evaluation of New 3, 5-Disubstituted-2-Thioxoimidazolidinones

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666171129213838 ◽

2018 ◽

Vol 18 (4) ◽

pp. 573-582 ◽

Cited By ~ 1

Author(s):

Khaled R.A. Abdellatif ◽

Mostafa M. Elbadawi ◽

Mohammed T. Elsaady ◽

Amer A. Abd El-Hafeez ◽

Takashi Fujimura ◽

...

Keyword(s):

Breast Cancer ◽

Cell Line ◽

Cell Lines ◽

Cancer Cell ◽

Topoisomerase I ◽

Cancer Cell Line ◽

Cytotoxic Agents ◽

Dependent Manner ◽

Human Lung Fibroblast ◽

Mcf 7

Background: Some 2-thioxoimidazolidinones have been reported as anti-prostate and anti-breast cancer agents through their inhibitory activity on topoisomerase I that is considered as a potential chemotherapeutic target. Objective: A new series of 3,5-disubstituted-2-thioxoimidazolidinone derivatives 10a-f and their S-methyl analogs 11a-f were designed, synthesized and evaluated for cytotoxicity against human prostate cancer cell line (PC-3), human breast cancer cell line (MCF-7) and non-cancerous human lung fibroblast cell line (WI-38). </P><P> Results and Method: While compounds 10a-f showed a broad range of activities against PC-3 and MCF-7 cell lines (IC50 = 34.0 – 186.9 and 24.6 – 147.5 µM respectively), the S-methyl analogs 11a-f showed (IC50 = 22.7 – 198.5 and 16.9 – 188.2 µM respectively) in comparison with 5-fluorouracil (IC50 = 60.7 and 40.7 µM respectively). 11c (IC50 = 22.7 and 29.2 µM) and 11f (IC50 = 28.7 and 16.9 µM) were the most potent among all compounds against both PC-3 and MCF-7 respectively with no cytotoxicity against WI-38. Conclusion: The newly synthesized compounds showed good activity against PC-3 and MCF-7 cell lines in comparison with 5-fluorouracil. Compounds 11c and 11f bound with human topoisomerase I similar to its known inhibitors and significantly inhibited its DNA relaxation activity in a dose dependent manner which may rationalize their molecular mechanism as cytotoxic agents.

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Mechanisms contributing to ado-trastuzumab emtansine (T-DM1)-induced toxicities: a gateway to better understanding ADC-associated toxicities

Antibody Therapeutics ◽

10.1093/abt/tbab005 ◽

2021 ◽

Author(s):

Yukinori Endo ◽

Nishant Mohan ◽

Milos Dokmanovic ◽

Wen Jin Wu

Keyword(s):

Breast Cancer ◽

Side Effects ◽

Metastatic Breast ◽

Invasive Disease ◽

Dependent Manner ◽

Trastuzumab Emtansine ◽

Antibody Drug Conjugate ◽

Her2 Positive ◽

Humanized Monoclonal Antibody ◽

Significant Efficacy

Abstract In order to improve the safety of novel therapeutic drugs, better understanding of the mechanisms of action is important. Ado-trastuzumab emtansine (also known as T-DM1) is an antibody-drug conjugate (ADC) consisting of a humanized monoclonal antibody directed against HER2 (trastuzumab) and a maytansinoid-derived toxin (DM1), which are linked by a non-cleavable thioether linker. T-DM1 has been approved for the treatment of trastuzumab-resistant HER2-positive metastatic breast cancer and recently for use as an adjuvant treatment option for patients with HER2-positive early breast cancer who have residual invasive disease. While the treatment with T-DM1 results in significant efficacy in the selected patient population, nonetheless, there are also concerns with the side effects such as thrombocytopenia and hepatotoxicity. While current understanding of the mechanism of T-DM1-mediated side effects is still incomplete, there have been several reports of HER2-dependent and/or -independent mechanisms that could be associated with the T-DM1-induced adverse events. The results from our laboratory show that T-DM1 binds to cytoskeleton-associated protein 5 (CKAP5) on the cell surface of hepatocytes via its payload component (DM1). This interaction is independent of HER2 and leads to cell growth inhibition and apoptosis of hepatocytes in a T-DM1 dose dependent manner. This review highlights the importance of HER2-independent mechanism of T-DM1 to induce hepatotoxicity, which offers a new insight into a role for CKAP5 in the overall maytansinoid-based ADC (DM1 and DM4)-mediated cytotoxicity. This discovery provides a molecular basis for T-DM1-induced off-target toxicity and opens a new avenue for developing the next generation of ADCs.

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Matrix Stiffness Modulates Metabolic Interaction between Human Stromal and Breast Cancer Cells to Stimulate Epithelial Motility

Metabolites ◽

10.3390/metabo11070432 ◽

2021 ◽

Vol 11 (7) ◽

pp. 432

Author(s):

Iván Ponce ◽

Nelson Garrido ◽

Nicolás Tobar ◽

Francisco Melo ◽

Patricio C. Smith ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Stromal Cells ◽

Glucose Transporter ◽

Lactate Production ◽

Resonance Energy ◽

Metabolic Reprogramming ◽

Dependent Manner ◽

Functional Link

Breast tumors belong to the type of desmoplastic lesion in which a stiffer tissue structure is a determinant of breast cancer progression and constitutes a risk factor for breast cancer development. It has been proposed that cancer-associated stromal cells (responsible for this fibrotic phenomenon) are able to metabolize glucose via lactate production, which supports the catabolic metabolism of cancer cells. The aim of this work was to investigate the possible functional link between these two processes. To measure the effect of matrix rigidity on metabolic determinations, we used compliant elastic polyacrylamide gels as a substrate material, to which matrix molecules were covalently linked. We evaluated metabolite transport in stromal cells using two different FRET (Fluorescence Resonance Energy Transfer) nanosensors specific for glucose and lactate. Cell migration/invasion was evaluated using Transwell devices. We show that increased stiffness stimulates lactate production and glucose uptake by mammary fibroblasts. This response was correlated with the expression of stromal glucose transporter Glut1 and monocarboxylate transporters MCT4. Moreover, mammary stromal cells cultured on stiff matrices generated soluble factors that stimulated epithelial breast migration in a stiffness-dependent manner. Using a normal breast stromal cell line, we found that a stiffer extracellular matrix favors the acquisition mechanistical properties that promote metabolic reprograming and also constitute a stimulus for epithelial motility. This new knowledge will help us to better understand the complex relationship between fibrosis, metabolic reprogramming, and cancer malignancy.

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Does coffee, tea and caffeine consumption reduce the risk of incident breast cancer? A systematic review and network meta-analysis

Public Health Nutrition ◽

10.1017/s1368980021000720 ◽

2021 ◽

pp. 1-13

Author(s):

Shu Wang ◽

Xiang Li ◽

Yue Yang ◽

Jingping Xie ◽

Mingyue Liu ◽

...

Keyword(s):

Breast Cancer ◽

Systematic Review ◽

Postmenopausal Women ◽

Meta Analysis ◽

High Dose ◽

Dependent Manner ◽

Tea Consumption ◽

Case Control Studies ◽

High Concentration ◽

Coffee Intake

Abstract Objective: We aimed to evaluate the association between coffee and/or tea consumption and breast cancer (BC) risk among premenopausal and postmenopausal women and to conduct a network meta-analysis. Design: Systematic review and network meta-analysis. Setting: We conducted a systematic review of electronic publications in the last 30 years to identify case–control studies or prospective cohort studies that evaluated the effects of coffee and tea intake. Results: Forty-five studies that included more than 3 323 288 participants were eligible for analysis. Network meta-analysis was performed to determine the effects of coffee and/or tea consumption on reducing BC risk in a dose-dependent manner and differences in coffee/tea type, menopause status, hormone receptor and the BMI in subgroup and meta-regression analyses. According to the first pairwise meta-analysis, low-dose coffee intake and high-dose tea intake may exhibit efficacy in preventing ER(estrogen receptor)− BC, particularly in postmenopausal women. Then, we performed another pairwise and network meta-analysis and determined that the recommended daily doses were 2–3 cups/d of coffee or ≥5 cups/d of tea, which contained a high concentration of caffeine, particularly in postmenopausal women. Conclusions: Coffee and tea consumption is not associated with a reduction in the overall BC risk in postmenopausal women and is associated with a potentially lower risk of ER− BC. And the highest recommended dose is 2–3 cups of coffee/d or ≥5 cups of tea/d. They are potentially useful dietary protectants for preventing BC.

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Antitumor Potential of Green Synthesized ZnONPs Using Root Extract of Withania somnifera against Human Breast Cancer Cell Line

Separations ◽

10.3390/separations8010008 ◽

2021 ◽

Vol 8 (1) ◽

pp. 8

Author(s):

Kollur Shiva Prasad ◽

Shashanka K Prasad ◽

Ravindra Veerapur ◽

Ghada Lamraoui ◽

Ashwini Prasad ◽

...

Keyword(s):

Breast Cancer ◽

Electron Microscopy ◽

Transmission Electron Microscopy ◽

Cell Line ◽

Withania Somnifera ◽

Root Extract ◽

Dependent Manner ◽

Sem Images ◽

Xrd Pattern ◽

Transmission Electron

Herein we report the synthesis of zinc oxide nanoparticles (ZnONPs) using Withania somnifera root extract (WSE) as an effective chelating agent. The microscopic techniques viz., X-ray diffraction analysis (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM), and selected area electron diffraction (SAED) were employed to analyze the as-obtained ZnONPs. The crystalline planes observed from the XRD pattern agrees with the hexagonal wurtzite structure of the as-prepared ZnONPs. The aggregations and agglomerations observed in the SEM images indicated that the size of the as-prepared ZnONPs was between 30 and 43 nm. The interplanar distance between the lattice fringes observed in the HRTEM image was found to be 0.253 nm, which is in good agreement with the (100) plane obtained in the XRD pattern. Furthermore, the anti-breast cancer cytotoxic evaluation was carried out using the MCF-7 cell line, and the results showed significant cytotoxic effects in a dose-dependent manner.

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Pro-inflammatory cytokine polymorphisms and interactions with dietary alcohol and estrogen, risk factors for invasive breast cancer using a post genome-wide analysis for gene–gene and gene–lifestyle interaction

Scientific Reports ◽

10.1038/s41598-020-80197-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Su Yon Jung ◽

Jeanette C. Papp ◽

Eric M. Sobel ◽

Matteo Pellegrini ◽

Herbert Yu ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Visceral Obesity ◽

Cumulative Exposure ◽

Environment Interaction ◽

Dependent Manner ◽

Nucleotide Polymorphisms ◽

Genome Wide ◽

Reduction Methods

AbstractMolecular and genetic immune-related pathways connected to breast cancer and lifestyles in postmenopausal women are not fully characterized. In this study, we explored the role of pro-inflammatory cytokines such as C-reactive protein (CRP) and interleukin-6 (IL-6) in those pathways at the genome-wide level. With single-nucleotide polymorphisms (SNPs) in the biomarkers and lifestyles together, we further constructed risk profiles to improve predictability for breast cancer. Our earlier genome-wide association gene-environment interaction study used large cohort data from the Women’s Health Initiative Database for Genotypes and Phenotypes Study and identified 88 SNPs associated with CRP and IL-6. For this study, we added an additional 68 SNPs from previous GWA studies, and together with 48 selected lifestyles, evaluated for the association with breast cancer risk via a 2-stage multimodal random survival forest and generalized multifactor dimensionality reduction methods. Overall and in obesity strata (by body mass index, waist, waist-to-hip ratio, exercise, and dietary fat intake), we identified the most predictive genetic and lifestyle variables. Two SNPs (SALL1 rs10521222 and HLA-DQA1 rs9271608) and lifestyles, including alcohol intake, lifetime cumulative exposure to estrogen, and overall and visceral obesity, are the most common and strongest predictive markers for breast cancer across the analyses. The risk profile that combined those variables presented their synergistic effect on the increased breast cancer risk in a gene–lifestyle dose-dependent manner. Our study may contribute to improved predictability for breast cancer and suggest potential interventions for the women with the risk genotypes and lifestyles to reduce their breast cancer risk.

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CRL4-DCAF12 Ubiquitin Ligase Controls MOV10 RNA Helicase during Spermatogenesis and T Cell Activation

International Journal of Molecular Sciences ◽

10.3390/ijms22105394 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5394

Author(s):

Tomas Lidak ◽

Nikol Baloghova ◽

Vladimir Korinek ◽

Radislav Sedlacek ◽

Jana Balounova ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Ubiquitin Ligase ◽

Cell Activation ◽

Rna Helicase ◽

Dependent Manner ◽

Amino Acid Residues ◽

Risc Complex ◽

Wide Range

Multisubunit cullin-RING ubiquitin ligase 4 (CRL4)-DCAF12 recognizes the C-terminal degron containing acidic amino acid residues. However, its physiological roles and substrates are largely unknown. Purification of CRL4-DCAF12 complexes revealed a wide range of potential substrates, including MOV10, an “ancient” RNA-induced silencing complex (RISC) complex RNA helicase. We show that DCAF12 controls the MOV10 protein level via its C-terminal motif in a proteasome- and CRL-dependent manner. Next, we generated Dcaf12 knockout mice and demonstrated that the DCAF12-mediated degradation of MOV10 is conserved in mice and humans. Detailed analysis of Dcaf12-deficient mice revealed that their testes produce fewer mature sperms, phenotype accompanied by elevated MOV10 and imbalance in meiotic markers SCP3 and γ-H2AX. Additionally, the percentages of splenic CD4+ T and natural killer T (NKT) cell populations were significantly altered. In vitro, activated Dcaf12-deficient T cells displayed inappropriately stabilized MOV10 and increased levels of activated caspases. In summary, we identified MOV10 as a novel substrate of CRL4-DCAF12 and demonstrated the biological relevance of the DCAF12-MOV10 pathway in spermatogenesis and T cell activation.

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