Here, we present new genetic and morphological evidence that human tumors consist of two distinct metabolic compartments. First, re-analysis genome-wide transcriptional profiling data revealed > 95 gene transcripts associated with mitochondrial biogenesis and/or translation were significantly elevated in breast cancer cells, as compared adjacent stromal tissue. Remarkably, nearly 40 these upregulated ribosomal proteins (MRPs), functionally protein components the OXPHOS complex. Second,...

Neural crest (NC) cells arise early in vertebrate development, migrate extensively and contribute to a diverse array of ectodermal mesenchymal derivatives. Previous models NC formation suggested derivation from neuralized ectoderm, via meso-ectodermal, or neural-non-neural ectoderm interactions. Recent studies using bird amphibian embryos suggest an earlier origin NC, independent neural mesodermal tissues. Here, we set out generate model which decipher signaling tissue interactions involved...

Here, we set out to test the novel hypothesis that increased mitochondrial biogenesis in epithelial cancer cells would "fuel" enhanced tumor growth. For this purpose, generated MDA-MB-231 (a triple-negative human breast cell line) overexpressing PGC-1α and MitoNEET, which are established molecules drive oxidative phosphorylation (OXPHOS). Interestingly, both MitoNEET abundance of OXPHOS protein complexes, conferred autophagy resistance under conditions starvation growth by up ~3-fold....

We have recently reported a series of Lys-covalent agents targeting the BIR3 domain X-linked inhibitor apoptosis protein (XIAP) using benzamide-sulfonyl fluoride warhead. Using XIAP as model system, we further investigated variety additional warheads that can be easily incorporated into binding peptides and analyzed their ability to form covalent adducts with lysine other amino acids, including tyrosine, histidine, serine, threonine, biochemical biophysical assays. Moreover, tested aqueous,...

Previously, we proposed a new paradigm to explain the compartment-specific role of autophagy in tumor metabolism. In this model, and mitochondrial dysfunction stroma promotes cellular catabolism, which results production recycled nutrients. These chemical building blocks high-energy “fuels” would then drive anabolic growth tumors, via resistance oxidative metabolism cancer cells. We have termed form stromal-epithelial metabolic coupling: “two-compartment metabolism.” Here, stringently tested...

EphA2 overexpression has been associated with metastasis in multiple cancer types, including melanomas and ovarian, prostate, lung, breast cancers. We have recently proposed the development of peptide–drug conjugates (PDCs) using agonistic EphA2-targeting agents, such as YSA peptide or its optimized version, 123B9. Although our studies indicated that YSA– 123B9–drug can selectively deliver cytotoxic drugs to cells vivo, relatively low cellular activities (i.e., high micromolar concentrations...

Cigarette smoke has been directly implicated in the disease pathogenesis of a plethora different human cancer subtypes, including breast cancers. The prevailing view is that cigarette acts as mutagen and DNA damaging agent normal epithelial cells, driving tumor initiation. However, its potential negative metabolic effects on stromal microenvironment have largely ignored. Here, we propose new mechanism by which carcinogen-rich may promote growth, metabolically "fertilizing" host...

Small-molecule inhibitors of DNA repair pathways are being intensively investigated as primary and adjuvant chemotherapies. We report the discovery that cardiac glycosides, natural products in clinical use for treatment heart failure atrial arrhythmia, potent double-strand break (DSB) repair. Our data suggest glycosides interact with phosphorylated mediator damage checkpoint protein 1 (phospho-MDC1) or E3 ubiquitin-protein ligase ring finger 8 (RNF8), two factors involved DSB repair, inhibit...

We have recently investigated the reactivity of aryl-fluorosulfates as warheads to form covalent adducts with Lys, Tyr, and His residues. However, rate reaction seemed relatively slow, putting into question their effectiveness in cell. Unlike previously reported agents that targeted a remote Lys residue respect target's binding site, current were designed more directly juxtapose an aryl-fluorosulfate is located within pocket BIR3 domain X-linked inhibitor apoptosis protein (XIAP). found such...

Pancreatic cancer is one of the deadliest cancers due to early rapid metastasis and chemoresistance. Recently, epithelial mesenchymal transition (EMT) was shown play a key role in pathogenesis pancreatic cancer. To understand caveolin-1 (Cav-1) EMT, we over-expressed Cav-1 cell line, Panc 10.05, that does not normally express Cav-1. Here, show expression cells induces an phenotype promotes cell-cell contact, with increased plasma membrane bound E-cadherin beta-catenin. Mechanistically, Snail...

Recently we reported that rapid determination of enthalpy binding can be achieved for a large number congeneric agents or in combinatorial libraries fairly efficiently. We show using thermodynamic Craig plot very useful dissecting the and entropy contribution different substituents on common scaffold, order to design potent, selective, pan-active compounds. In our implementation, approach identified critical Lys residue BIR3 domain XIAP. report first time it is possible target such...

Triple-negative breast cancer (TNBC) poses significant clinical challenges due to its high heterogeneity, with multiple subtypes exhibiting distinct molecular characteristics and treatment responses. The development of resistance chemotherapy targeted therapies remains a major obstacle, identifying reliable biomarkers predict therapeutic response continues be challenging. This study aims enhance the delivery immunostimulant Toll-like receptor 7/8 (TLR7/8) agonist resiquimod (R848) using safe...

Chronic renal failure is known to cause various nail pathologies. They may be directly related the condition itself or its complications therapy.To compare changes in end-stage patients under haemodialysis with healthy persons and study potential relationship parameters patients.The comprised 100 chronic regular as well control subjects of matched age sex. Both groups were subjected full history taking thorough general examination. Complete blood picture, liver kidney function tests fasting...

Our recent studies have mechanistically demonstrated that cancer-associated fibroblasts (CAFs) produce energy-rich metabolites functionally support the growth of cancer cells. Also, several authors DNA instability in tumor stroma greatly contributes to carcinogenesis. To further test this hypothesis, we stably knocked-down BRCA1 expression human hTERT-immortalized (shBRCA1) using an shRNA lentiviral approach. As expected, shBRCA1 displayed elevated rate. Using immunofluorescence and...

Most cancer therapies involve a component of treatment that inflicts DNA damage in tumor cells, such as double-strand breaks (DSBs), which are considered the most serious threat to genomic integrity. Complex systems have evolved repair these lesions, and successful DSB is essential for cell survival after exposure ionizing radiation (IR) other DNA-damaging agents. As such, inhibition potentially efficacious strategy chemo- radiosensitization. Homologous recombination (HR) nonhomologous...

Upregulation of antiapoptotic Bcl-2 proteins in certain tumors confers cancer cell resistance to chemotherapy or radiations. Members the proteins, including Bcl-2, Mcl-1, Bcl-xL, Bcl-w, and Bfl-1, inhibit apoptosis by selectively binding conserved α-helical regions, named BH3 domains, pro-apoptotic such as Bim, tBid, Bad, NOXA. Five have been identified that interact with various selectivity containing counterparts. Cancer cells present variable levels these making design effective based...

EphA2 overexpression is invariably associated with poor prognosis and development of aggressive metastatic cancers in pancreatic, prostate, lung, ovarian, breast melanoma. Recent efforts from our laboratories identified a number agonistic peptides targeting the ligand-binding domain receptor. The individual agents, however, were still relatively weak affinities (micromolar range) that precluded detailed structural studies on mode action. Using systematic optimization 12-mer peptide mimetic...

Liver cirrhosis, hepatitis C virus (HCV) and B (HBV) infections are known to be associated with different skin disorders. Nail changes additional important criteria, which would help in identification of these systemic diseases.To record the nail abnormalities patients liver disease were not reported before, especially those HCV HBV infection.The study comprised 100 HCV, cell failure, normal healthy controls. Both groups underwent full history taking thorough general examination, complete...

Here, we provide the necessary proof of concept, that it is possible to metabolically create a non-permissive or "hostile" stromal microenvironment, which actively prevents tumor engraftment in vivo. We developed novel genetically engineered fibroblast cell line completely formation mice, with 100% protection rate. No host side effects were apparent. This could represent viable cellular strategy for preventing and treating variety human cancers. More specifically, examined autocrine...

The EphA2 tyrosine kinase receptor is highly expressed in several types of solid tumors. In our recent studies, we targeted pancreatic cancer with agonistic agents and demonstrated that suppression significantly reduced cancer-cell migration cell-based assays. the present study, focused on targeting prostate cancer. While not all cancers express EphA2, showed enzalutamide induced expression cells a patient-derived xenograft (PDX) animal model, which provides further impetus to target Western...

Recently we reported on aryl-fluorosulfates as possible stable and effective electrophiles for the design of lysine covalent, cell permeable antagonists protein-protein interactions (PPIs). Here revisit use aryl-sulfonyl fluorides Lys-targeting moieties, incorporating these in XIAP (X-linked inhibitor apoptosis protein) targeting agents. We evaluated stability buffer reactivity with Lys311 various using biochemical biophysical approaches, including displacement assays, mass spectrometry, SDS...