Publications by authors named "Elena Strekalova"

Purpose: Tumor cells are dependent on the glutathione and thioredoxin antioxidant pathways to survive oxidative stress. Since the essential amino acid methionine is converted to glutathione, we hypothesized that methionine restriction (MR) would deplete glutathione and render tumors dependent on the thioredoxin pathway and its rate-limiting enzyme thioredoxin reductase (TXNRD).

Methods: Triple (ER/PR/HER2)-negative breast cancer (TNBC) cells were treated with control or MR media and the effects on reactive oxygen species (ROS) and antioxidant signaling were examined.

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Purpose: Transformed cells are vulnerable to depletion of certain amino acids. Lysine oxidase (LO) catalyzes the oxidative deamination of lysine, resulting in lysine depletion and hydrogen peroxide production. Although LO has broad antitumor activity in preclinical models, the cytotoxic mechanisms of LO are poorly understood.

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We have developed a novel therapeutic paradigm ("metabolic priming") for cancer whereby restriction of the essential amino acid methionine activates a number of cell-stress-response pathways that can be selectively targeted to enhance the therapeutic impact of methionine restriction. One example of metabolic priming is the combination of methionine restriction with proapoptotic TRAIL receptor-2 (TRAIL-R2) agonists. Methionine restriction enhances the cell surface expression of TRAIL-R2 selectively in transformed breast epithelial cells and renders them more susceptible to cell death induction by TRAIL-R2 agonists in cellular and murine models of breast cancer.

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Purpose: Many transformed cells and embryonic stem cells are dependent on the biosynthesis of the universal methyl-donor S-adenosylmethionine (SAM) from methionine by the enzyme MAT2A to maintain their epigenome. We hypothesized that cancer stem cells (CSCs) rely on SAM biosynthesis and that the combination of methionine depletion and MAT2A inhibition would eradicate CSCs.

Methods: Human triple (ER/PR/HER2)-negative breast carcinoma (TNBC) cell lines were cultured as CSC-enriched mammospheres in control or methionine-free media.

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Purpose: Despite robust antitumor activity in diverse preclinical models, TNF-related apoptosis-inducing ligand (TRAIL) receptor agonists have not demonstrated efficacy in clinical trials, underscoring the need to identify agents that enhance their activity. We postulated that the metabolic stress induced by the diabetes drug metformin would sensitize breast cancer cells to TRAIL receptor agonists.

Methods: Human triple (estrogen receptor, progesterone receptor, and HER2)-negative breast cancer (TNBC) cell lines were treated with TRAIL receptor agonists (monoclonal antibodies or TRAIL peptide), metformin, or the combination.

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αB-crystallin is a widely expressed member of the small heat shock protein family that protects cells from stress by its dual function as a molecular chaperone to preserve proteostasis and as a cell death antagonist that negatively regulates components of the conserved apoptotic cell death machinery. Deregulated expression of αB-crystallin occurs in a broad array of solid tumors and has been linked to tumor progression and poor clinical outcomes. This review will focus on new insights into the molecular mechanisms by which oncogenes, oxidative stress, matrix detachment and other tumor microenvironmental stressors deregulate αB-crystallin expression.

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Gating of mesoporous silica nanoparticles (MSNs) with the stimuli-responsive poly(β-amino ester) has been achieved. This hybrid nanocarrier releases doxorubicin (DOX) under acidic conditions or in the presence of porcine liver esterase. The DOX loaded poly(β-amino ester)-capped MSNs reduce cell viability when tested on MDA-MB-231 human breast cancer cells.

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Purpose: Many neoplasms are vulnerable to methionine deficiency by mechanisms that are poorly understood. Because gene profiling studies have revealed that methionine depletion increases TNF-related apoptosis-inducing ligand receptor-2 (TRAIL-R2) mRNA, we postulated that methionine stress sensitizes breast cancer cells to proapoptotic TRAIL-R2 agonists.

Experimental Design: Human triple (ER/PR/HER2)-negative breast carcinoma cell lines were cultured in control or methionine-free media.

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Metastasis portends a poor prognosis for cancer patients. Primary tumor cells disseminate through the bloodstream before the appearance of detectable metastatic lesions. The analysis of cancer cells in blood—so-called circulating tumor cells (CTCs)—may provide unprecedented opportunities for metastatic risk assessment and investigation.

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Purpose: Basal-like breast tumors are typically (ER/PR/HER2) triple-negative and are associated with a high incidence of brain metastases and poor clinical outcomes. The molecular chaperone αB-crystallin is predominantly expressed in triple-negative breast cancer (TNBC) and contributes to an aggressive tumor phenotype in preclinical models. We investigated the potential role of αB-crystallin in brain metastasis in TNBCs.

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Ruthenium(II) polypyridyl complexes have emerged both as promising probes of DNA structure and as anticancer agents because of their unique photophysical and cytotoxic properties. A key consideration in the administration of those therapeutic agents is the optimization of their chemical reactivities to allow facile attack on the target sites, yet avoid unwanted side effects. Here, we present a drug delivery platform technology, obtained by grafting the surface of mesoporous silica nanoparticles (MSNPs) with ruthenium(II) dipyridophenazine (dppz) complexes.

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Dysregulation of the proteolytic processing of amyloid precursor protein by γ-secretase and the ensuing generation of amyloid-β is associated with the pathogenesis of Alzheimer's disease. Thus, the identification of amyloid precursor protein binding proteins involved in regulating processing of amyloid precursor protein by the γ-secretase complex is essential for understanding the mechanisms underlying the molecular pathology of the disease. We identified calreticulin as novel amyloid precursor protein interaction partner that binds to the γ-secretase cleavage site within amyloid precursor protein and showed that this Ca(2+)- and N-glycan-independent interaction is mediated by amino acids 330-344 in the C-terminal C-domain of calreticulin.

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In order to investigate the cryoprotective mechanism of trehalose on proteins, we use molecular dynamics computer simulations to study the microscopic dynamics of water upon cooling in an aqueous solution of lysozyme and trehalose. We find that the presence of trehalose causes global retardation of the dynamics of water. Comparing aqueous solutions of lysozyme with/without trehalose, we observe that the dynamics of water in the hydration layers close to the protein is dramatically slower when trehalose is present in the system.

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The complex behavior of liquid water, along with its anomalies and their crucial role in the existence of life, continue to attract the attention of researchers. The anomalous behavior of water is more pronounced at subfreezing temperatures and numerous theoretical and experimental studies are directed towards developing a coherent thermodynamic and dynamic framework for understanding supercooled water. The existence of a liquid-liquid critical point in the deep supercooled region has been related to the anomalous behavior of water.

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Using molecular dynamics simulations, we investigate the effects of different nanoconfinements on complex liquids-e.g., colloids or protein solutions-with density anomalies and a liquid-liquid phase transition (LLPT).

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The 5-hydroxytryptamine type 4 receptor (5-HT(4)R) regulates many physiological processes, including learning and memory, cognition, and gastrointestinal motility. Little is known about its role in angiogenesis. Using mouse hindlimb ischemia model of angiogenesis, we observed a significant reduction of limb blood flow recovery 14 days after ischemia and a decrease in density of CD31-positive vessels in adductor muscles in 5-HT(4)R(-/-) mice compared to wild type littermates.

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Using Monte Carlo simulations, we study a coarse-grained model of a water layer confined in a fixed disordered matrix of hydrophobic nanoparticles at different particle concentrations c. For c=0, we find a first-order liquid-liquid phase transition (LLPT) ending in one critical point at low pressure P. For c>0, our simulations are consistent with a LLPT line ending in two critical points at low and high P.

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The alpha subunit of heterotrimeric G13 protein is required for the embryonic angiogenesis (Offermanns et al., Science 275:533-536, 1997). However, the molecular mechanism of Galpha13-dependent angiogenesis is not understood.

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