STAT1 potentiates oxidative stress revealing a targetable vulnerability that increases phenformin efficacy in breast cancer.
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ABSTRACT:
SUBMITTER: Totten SP
PROVIDER: S-EPMC8175605 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundIn preclinical studies, the combination of chronic stress and a high sugar/fat diet is a more potent driver of visceral adiposity than diet alone, a process mediated by peripheral neuropeptide Y (NPY).MethodsIn a human model of chronic stress, we investigated whether the synergistic combination of highly palatable foods (HPF; high sugar/fat) and stress was associated with elevated metabolic risk. Using a case-control design, we compared 33 post-menopausal caregivers (the chronic stress group) to 28 age-matched low-stress control women on reported HPF consumption (modified Block Food Frequency Questionnaire), waistline circumference, truncal fat ultrasound, and insulin sensitivity using a 3-h oral glucose tolerance test. A fasting blood draw was assayed for plasma NPY and oxidative stress markers (8-hydroxyguanosine and F2-Isoprostanes).ResultsAmong chronically stressed women only, greater HPF consumption was associated with greater abdominal adiposity, oxidative stress, and insulin resistance at baseline (all p's≤.01). Furthermore, plasma NPY was significantly elevated in chronically stressed women (p<.01), and the association of HPF with abdominal adiposity was stronger among women with high versus low NPY. There were no significant predictions of change over 1-year, likely due to high stability (little change) in the primary outcomes over this period.DiscussionChronic stress is associated with enhanced vulnerability to diet-related metabolic risk (abdominal adiposity, insulin resistance, and oxidative stress). Stress-induced peripheral NPY may play a mechanistic role.
| S-EPMC4104274 | biostudies-literature
Project description:The effect of preconception drinking by the mother on the life-long health outcomes of her children is not known, and therefore, in this study using an animal model, we determined the impact of preconception alcohol drinking of the mother on offspring stress response during adulthood. In our preconception alcohol exposure model, adult female rats were fed with 6.7% alcohol in their diet for 4 weeks, went without alcohol for 3 weeks and were bred to generate male and female offspring. Preconception alcohol-exposed offsprings' birth weight, body growth, stress response, anxiety-like behaviors, and changes in stress regulatory gene and protein hormone levels were evaluated. In addition, roles of epigenetic mechanisms in preconception alcohol effects were determined. Alcohol feeding three weeks prior to conception significantly affected pregnancy outcomes of female rats, with respect to delivery period and birth weight of offspring, without affecting maternal care behaviors. Preconception alcohol negatively affected offspring adult health, producing an increased stress hormone response to an immune challenge. In addition, preconception alcohol was associated with changes in expression and methylation profiles of stress regulatory genes in various brain areas. These changes in stress regulatory genes were normalized following treatment with a DNA methylation blocker during the postnatal period. These data highlight the novel possibility that preconception alcohol affects the inheritance of stress-related diseases possibly by epigenetic mechanisms.
| S-EPMC5026748 | biostudies-literature
Project description:Brain serotonin (5-HT) deficiency and exposure to psychosocial stress have both been implicated in the etiology of depression and anxiety disorders, but whether 5-HT deficiency influences susceptibility to depression- and anxiety-like phenotypes induced by psychosocial stress has not been formally established. Most clinically effective antidepressants increase the extracellular levels of 5-HT, and thus it has been hypothesized that antidepressant responses result from the reversal of endogenous 5-HT deficiency, but this hypothesis remains highly controversial. Here we evaluated the impact of brain 5-HT deficiency on stress susceptibility and antidepressant-like responses using tryptophan hydroxylase 2 knockin (Tph2KI) mice, which display 60-80% reductions in brain 5-HT. Our results demonstrate that 5-HT deficiency leads to increased susceptibility to social defeat stress (SDS), a model of psychosocial stress, and prevents the fluoxetine (FLX)-induced reversal of SDS-induced social avoidance, suggesting that 5-HT deficiency may impair antidepressant responses. In light of recent clinical and preclinical studies highlighting the potential of inhibiting the lateral habenula (LHb) to achieve antidepressant and antidepressant-like responses, we also examined whether LHb inhibition could achieve antidepressant-like responses in FLX-insensitive Tph2KI mice subjected to SDS. Our data reveal that using designer receptors exclusively activated by designer drugs (DREADDs) to inhibit LHb activity leads to reduced SDS-induced social avoidance behavior in both WT and Tph2KI mice. This observation provides additional preclinical evidence that inhibiting the LHb might represent a promising alternative therapeutic approach under conditions in which selective 5-HT reuptake inhibitors are ineffective.
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Project description:Ferroptosis has emerged as an attractive strategy in cancer therapy. Understanding the operational networks regulating ferroptosis may unravel vulnerabilities that could be harnessed for therapeutic benefit. Using CRISPR-activation screens in ferroptosis hypersensitive cells, we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN-amplified neuroblastoma cells from ferroptosis. Genetic deletion of LRP8 leads to ferroptosis as a result of an insufficient supply of selenocysteine, which is required for the translation of the anti-ferroptotic selenoprotein GPX4. This dependency is caused by low expression of alternative selenium uptake pathways such as system Xc-. The identification of LRP8 as a specific vulnerability of MYCN-amplified neuroblastoma cells was confirmed in constitutive and inducible LRP8 knockout orthotopic xenografts. These findings disclose a yet-unaccounted mechanism of selective ferroptosis induction that might be explored as a therapeutic strategy for high-risk neuroblastoma and potentially other MYCN-amplified entities.
| S-SCDT-10_15252-EMMM_202318014 | biostudies-other
Project description:SLC7A11-mediated cystine uptake is critical for maintaining redox balance and cell survival. Here we show that this comes at a significant cost for cancer cells with high levels of SLC7A11. Actively importing cystine is potentially toxic due to its low solubility, forcing cancer cells with high levels of SLC7A11 (SLC7A11high) to constitutively reduce cystine to the more soluble cysteine. This presents a significant drain on the cellular NADPH pool and renders such cells dependent on the pentose phosphate pathway. Limiting glucose supply to SLC7A11high cancer cells results in marked accumulation of intracellular cystine, redox system collapse and rapid cell death, which can be rescued by treatments that prevent disulfide accumulation. We further show that inhibitors of glucose transporters selectively kill SLC7A11high cancer cells and suppress SLC7A11high tumour growth. Our results identify a coupling between SLC7A11-associated cystine metabolism and the pentose phosphate pathway, and uncover an accompanying metabolic vulnerability for therapeutic targeting in SLC7A11high cancers.
| S-EPMC7194135 | biostudies-literature
Project description:Sorafenib is the first developed systemic treatment for advanced forms of hepatocellular carcinoma, which constitutes the most frequent form of primary liver cancers and is a major global health burden. Although statistically significant, the positive effect of sorafenib on median survival remains modest, highlighting the need to develop novel therapeutic approaches. In this report, we introduce diclofenac, a nonsteroidal anti-inflammatory drug, as a potent catalyzer of sorafenib anticancer efficacy. Treatment of three different hepatocellular cancer cells (Huh-7, HepG2, and PLC-PRF-5) with sorafenib (5 µM, 24 h) and diclofenac (100 µM, 24 h) significantly increased cancer cell death compared to sorafenib or diclofenac alone. Anti-oxidant compounds, including N-acetyl-cysteine and ascorbic acid, reversed the deleterious effects of diclofenac/sorafenib co-therapy, suggesting that the generation of toxic levels of oxidative stress was responsible for cell death. Accordingly, whereas diclofenac increased production of mitochondrial oxygen reactive species, sorafenib decreased concentrations of glutathione. We further show that tumor burden was significantly diminished in mice bearing tumor xenografts following sorafenib/diclofenac co-therapy when compared to sorafenib or diclofenac alone. Taken together, these results highlight the anticancer benefits of sorafenib/diclofenac co-therapy in hepatocellular carcinoma. They further indicate that combining sorafenib with compounds that increase oxidative stress represents a valuable treatment strategy in hepatocellular carcinoma.
| S-EPMC6827164 | biostudies-literature
Project description:Oxidative stress is key in the pathogenesis of several diseases including age-related macular degeneration (AMD), atherosclerosis, diabetes, and Alzheimer's disease. It has previously been established that a lipid peroxidation product, carboxyethylpyrrole (CEP), accumulates in the retinas of AMD patients. Retinal infiltrating macrophages also accumulate in the retinas of both AMD patients and in a murine model of AMD. We therefore investigated the ability of CEP-adducts to activate innate immune signaling in murine bone-marrow derived macrophages (BMDMs). We found that CEP specifically synergizes with low-dose TLR2-agonists (but not agonists for other TLRs) to induce production of inflammatory cytokines. Moreover, CEP selectively augments TLR2/TLR1-signaling instead of TLR2/TLR6-signaling. These studies uncover a novel synergistic inflammatory relationship between an endogenously produced oxidation molecule and a pathogen-derived product, which may have implications in the AMD disease process and other oxidative stress-driven pathologies.
| S-EPMC4153630 | biostudies-literature
Project description:Pro-survival members of the BCL-2 family, including MCL-1, are emerging as important proteins during the development and therapeutic response of solid tumors. Notably, high levels of MCL-1 occur in breast cancer, where functional dependency has been demonstrated using cell lines and mouse models. The utility of restoring apoptosis in cancer cells through inhibition of pro-survival BCL-2 proteins has been realized in the clinic, where the first specific inhibitor of BCL-2 is approved for use in leukemia. A variety of MCL-1 inhibitors are now undergoing clinical trials for blood cancer treatment and application of this new class of drugs is also being tested in solid cancers. On-target compounds specific to MCL-1 have demonstrated promising efficacy in preclinical models of breast cancer and show potential to enhance the anti-tumor effect of conventional therapies. Taken together, this makes MCL-1 an extremely attractive target for clinical evaluation in the context of breast cancer.Abbreviations: ADC (antibody-drug conjugate); AML (Acute myeloid leukemia); APAF1 (apoptotic protease activating factor 1); bCAFs (breast cancer associated fibroblasts); BCL-2 (B-cell lymphoma 2); BH (BCL-2 homology); CLL (chronic lymphocytic leukemia); EGF (epidermal growth factor); EMT (epithelial to mesenchymal transition); ER (estrogen receptor); FDA (food and drug administration); GEMM (genetically engineered mouse model); HER2 (human epidermal growth factor 2); IL6 (interleukin 6); IMM (inner mitochondrial membrane); IMS (intermembrane space); MCL-1 (myeloid cell leukemia-1); MOMP (mitochondrial outer membrane permeabilisation); MM (multiple myeloma); PDX (patient-derived xenograft); OMM (outer mitochondrial membrane); PROTAC (proteolysis-targeting chimeras) TNBC (triple negative breast cancer); UPS (ubiquitin mediated proteolysis system).
| S-EPMC9278428 | biostudies-literature
Project description:Successful cancer therapy is contingent on identifying cancer-specific aberrant phenotypes and their associated vulnerabilities. We recently reported that a subset of almost every cancer type contains a genome-wide defect in RNA Polymerase II-mediated transcription elongation (TEdef), which impairs the expression of long genes and confers resistance to anti-tumor immune attack. Using a combination of computational analysis and laboratory experiments, we report that tumor cells with TEdef have widespread overexpression of the components of the protein homeostasis machinery (mostly composed of short genes), including protein folding and clearance. Accordingly, TEdef cells were characterized by abnormally high levels of insoluble protein aggregates in the cytoplasm and autophagy influx. We present evidence that TEdef cells exhibit impaired clearance of misfolded protein aggregates through the ubiquitin-proteasome system, and thus rely on autophagy for their degradation. As such, while these cells were highly resistant to proteasome inhibitors, they were acutely sensitive to inhibitors of autophagy in vitro and in vivo. This study reveals a major aberrant phenotype that is observed in ∼15-25% of all cancers and characterizes a unique cellular vulnerability that can be readily exploited in the clinic to improve treatment efficacy.
| S-EPMC8718660 | biostudies-literature
Project description:There is an unmet need for new antimitotic drug combinations that target cancer-specific vulnerabilities. Based on our finding of elevated biomolecule oxidation in mitotically arrested cancer cells, we combined Plk1 inhibitors with TH588, an MTH1 inhibitor that prevents detoxification of oxidized nucleotide triphosphates. This combination showed robust synergistic killing of cancer, but not normal, cells that, surprisingly, was MTH1-independent. To dissect the underlying synergistic mechanism, we developed VISAGE, a strategy integrating experimental synergy quantification with computational-pathway-based gene expression analysis. VISAGE predicted, and we experimentally confirmed, that this synergistic combination treatment targeted the mitotic spindle. Specifically, TH588 binding to β-tubulin impaired microtubule assembly, which when combined with Plk1 blockade, synergistically disrupted mitotic chromosome positioning to the spindle midzone. These findings identify a cancer-specific mitotic vulnerability that is targetable using Plk1 inhibitors with microtubule-destabilizing agents and highlight the general utility of the VISAGE approach to elucidate molecular mechanisms of drug synergy.
| S-EPMC6688637 | biostudies-literature