A5005574192- Heat shock proteins research
- Enzyme function and inhibition
- Helicobacter pylori-related gastroenterology studies
- Inflammatory mediators and NSAID effects
- Lung Cancer Treatments and Mutations
- Gastric Cancer Management and Outcomes
- Colorectal and Anal Carcinomas
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Endoplasmic Reticulum Stress and Disease
- ATP Synthase and ATPases Research
- Pancreatic and Hepatic Oncology Research
- Enzyme Structure and Function
- Colorectal Cancer Surgical Treatments
- Cancer-related gene regulation
- Epigenetics and DNA Methylation
- Acute Myeloid Leukemia Research
- Adenosine and Purinergic Signaling
- thermodynamics and calorimetric analyses
- Colorectal Cancer Treatments and Studies
- Biochemical and Molecular Research
- Chemical Reactions and Isotopes
- Cell death mechanisms and regulation
- Neuroendocrine Tumor Research Advances
- Histone Deacetylase Inhibitors Research
- T-cell and Retrovirus Studies
Daiichi-Sankyo (Japan)
2019-2025
Hirosaki National Hospital
2021-2024
Daiichi Sankyo (United States)
2023
Hirosaki University
2009-2017
Aomori Prefectural Central Hospital
2016-2017
National Cancer Institute
2007-2016
Center for Cancer Research
2007-2016
National Institutes of Health
2012-2015
SUNY Upstate Medical University
2013
Cancer Research Institute
2013
Significance TNF receptor-associated protein (TRAP1) is found predominantly in mitochondria. A possible direct impact of TRAP1 on mitochondrial metabolism remains unexplored. We used TRAP1-null cells and transient silencing/overexpression to show that regulates a metabolic switch between oxidative phosphorylation aerobic glycolysis immortalized mouse fibroblasts human tumor cells. deficiency promotes increased respiration, fatty acid oxidation, tricarboxylic cycle intermediates, ATP reactive...
Epigenomes enable the rectification of disordered cancer gene expression, thereby providing new targets for pharmacological interventions. The clinical utility targeting histone H3 lysine trimethylation (H3K27me3) as an epigenetic hallmark has been demonstrated
Hsp90 is an essential and highly conserved modular molecular chaperone whose N middle domains are separated by a disordered region termed the charged linker. Although its importance has been previously disregarded, because minimal linker length sufficient for activity, evolutionary persistence of extensive linkers divergent sequence in proteins most eukaryotes remains unexplained. To examine this question further, we introduced human plasmodium native length-matched artificial into yeast...
Prostaglandin E2(PGE2) has a strong protective effect on the gastric mucosain vivo; however, molecular mechanism of direct cytoprotective PGE2 mucosal cells yet to be elucidated. Although we reported previously that inhibited irritant-induced apoptotic DNA fragmentation in primary cultures guinea pig cells, show here inhibits ethanol-dependent release cytochrome c from mitochondria. Of four main subtypes receptors, also demonstrated, using subtype-specific agonists, EP2 and EP4 receptors are...
We report the discovery of a potent and isozyme-selective MTHFD2 inhibitor, DS18561882 (2). Through investigation substituents on our tricyclic coumarin scaffold (1,2,3,4-tetrahydrochromeno[3,4-c]pyridin-5-one), inhibitory activity was shown to be elevated by incorporating an amine moiety at 8-position methyl group 7-position initial lead 1. X-ray structure analysis revealed that key interaction for enhanced potency salt bridge formation between diphosphate linker NAD+ cofactor. Furthermore,...
The molecular chaperone Hsp90 protects deregulated signaling proteins that are vital for tumor growth and survival. Tumors generally display sensitivity selectivity toward inhibitors; however, the mechanism underlying this phenotype remains undefined. We report mitotic checkpoint kinase Mps1 phosphorylates a conserved threonine residue in amino-domain of Hsp90. This, turn, regulates function by reducing ATPase activity while fostering association with clients, including Mps1. Phosphorylation...
Mixed lineage leukemia 1-rearranged (MLL1-r) acute patients respond poorly to currently available treatments and there is a need develop more effective therapies directly disrupting the Menin‒MLL1 complex. Small-molecule-mediated inhibition of protein‒protein interaction between Menin MLL1 fusion proteins potential therapeutic strategy for with MLL1-r or mutated-nucleophosmin 1 (NPM1c) leukemia. In this study, we preclinically evaluated new compound DS-1594a its salts.We preclinical efficacy...
We recently reported that nonsteroidal anti-inflammatory drug (NSAID)-induced gastric lesions involve NSAID-induced apoptosis of mucosal cells, which in turn involves the endoplasmic reticulum stress response, particular up-regulation CCAAT/enhancer-binding protein homologous transcription factor (CHOP). In this study, we have examined molecular mechanism governing primary cultures cells. Various NSAIDs showed membrane permeabilization activity correlated with their apoptosis-inducing...
Hsp90 inhibitors are being evaluated extensively in patients with advanced cancers. However, the impact of inhibition on signaling pathways normal tissues and effect that this may have antitumor activity these molecularly targeted drugs not been rigorously examined. Breast prostate carcinomas among those cancers respond to animal xenograft models early studies patients. Because frequently metastasize bone, it is important determine bone environment. In current study, we show that, contrast...
Gastric mucosal cell death by non-steroidal anti-inflammatory drugs (NSAID11113) is suggested to be involved in NSAID-induced gastric lesions. Therefore, cellular factors that suppress this are important for protection of the mucosa from NSAIDs. Heme oxygenase-1 (HO-1) up-regulated various stressors and protects cells against stressors. Here, we have examined up-regulation HO-1 NSAIDs contribution both vitro vivo. In cultured cells, all tested HO-1. rats, orally administered indomethacin...
Heat Shock Protein 90 (Hsp90) is an essential molecular chaperone in eukaryotic cells, and it maintains the functional conformation of a subset proteins that are typically key components multiple regulatory signaling networks mediating cancer cell proliferation, survival, metastasis. It possible to selectively inhibit Hsp90 using natural products such as geldanamycin (GA) or radicicol (RD), which have served prototypes for development synthetic inhibitors. These compounds bind within...
The proto-oncogene MET is aberrantly activated via overexpression or mutation in numerous cancers, making it a prime anticancer molecular target. However, the clinical success of MET-directed tyrosine kinase inhibitors (TKI) has been limited due, part, to mutations domain that confer therapeutic resistance. Circumventing this problem remains key challenge improving durable responses patients receiving MET-targeted therapy. an HSP90-dependent kinase, and report we show HSP90 preferentially...
The two cytosolic/nuclear isoforms of the molecular chaperone HSP90, stress-inducible HSP90α and constitutively expressed HSP90β, fold, assemble maintain three-dimensional structure numerous client proteins. Because many HSP90 clients are important in cancer, several inhibitors have been evaluated clinic. However, little is known concerning possible unique isoform or conformational preferences either individual inhibitors. In this report, we compare relative interaction strength both HSP90β...
A major clinical problem encountered with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin is gastropathy. In this study, we examined, using guinea pig gastric mucosal cells in primary culture, how NSAIDs damage cells. The short-term treatment high concentrations decreased cell viability absence apoptotic DNA fragmentation, chromatin condensation, or caspase activation. Cells lost membrane integrity treatment, suggesting that induced necrosis under these...