A5034128364- Sphingolipid Metabolism and Signaling
- Protein Kinase Regulation and GTPase Signaling
- Microtubule and mitosis dynamics
- Lipid Membrane Structure and Behavior
- Cellular transport and secretion
- Glycosylation and Glycoproteins Research
- Erythrocyte Function and Pathophysiology
- Cancer-related Molecular Pathways
- Acute Lymphoblastic Leukemia research
- Phagocytosis and Immune Regulation
- Autophagy in Disease and Therapy
- PI3K/AKT/mTOR signaling in cancer
- Cell death mechanisms and regulation
- Virus-based gene therapy research
- Endoplasmic Reticulum Stress and Disease
- Acute Myeloid Leukemia Research
- Protease and Inhibitor Mechanisms
- Cannabis and Cannabinoid Research
- Histone Deacetylase Inhibitors Research
- Cell Adhesion Molecules Research
- Protein Degradation and Inhibitors
- Melanoma and MAPK Pathways
- Receptor Mechanisms and Signaling
- Immune Cell Function and Interaction
- 14-3-3 protein interactions
Penn State Milton S. Hershey Medical Center
2007-2024
Pennsylvania State University
2011-2024
National Center for Advancing Translational Sciences
2023
Hershey (United States)
2015
University of Virginia Cancer Center
2015
University of Virginia
2015
Cancer Research Foundation
2007
Sphingosine kinase 1 (SphK1) is an oncoprotein capable of directly transforming cells and associated with resistance to chemotherapy radiotherapy. SphK1 increased in various human cancers; whereas, blockade restores sensitivity therapeutic killing resistant cancer cell lines. We investigated expression clinical tissue samples from patients non-Hodgkin lymphomas (NHL). Tissues 69 either NHL (n = 44) or reactive lymphoid hyperplasias (RH) 25) were examined for protein by Western blot...
Resistance to therapies develops rapidly for melanoma leading more aggressive disease. Therefore, agents are needed that specifically inhibit proteins or pathways controlling the development of this disease, which can be combined, dependent on genes deregulated in a particular patient's tumors. This study shows elevated sphingosine-1-phosphate (S-1-P) levels resulting from increased activity sphingosine kinase-1 (SPHK1) occur advanced melanomas. Targeting SPHK1 using siRNA decreased...
We previously developed SKI-178 (<i>N</i>′-[(1<i>E</i>)-1-(3,4-dimethoxyphenyl)ethylidene]-3-(4-methoxxyphenyl)-1<i>H</i>-pyrazole-5-carbohydrazide) as a novel sphingosine kinase-1 (SphK1) selective inhibitor and, herein, sought to determine the mechanism-of-action of SKI-178–induced cell death. Using human acute myeloid leukemia (AML) lines model, we present evidence that induces prolonged mitosis followed by apoptotic death through intrinsic cascade. Further examination mechanism action...
Tumor-associated inflammation mediates the development of a systemic immunosuppressive milieu that is major obstacle to effective treatment cancer. Inflammation has been shown promote expansion immature myeloid cells which have exert activity in laboratory models cancer as well patients. Consequentially, significant effort underway toward therapies decrease tumor-associated and cells. The current study demonstrated previously described deep tissue imaging modality, utilized indocyanine...
Sphingolipid metabolism has been identified as a potential therapeutic target in cancer. Sphingosine-1-phosphate (S1P) is potent bioactive sphingolipid metabolite produced by sphingosine kinases-1 and −2 (SPHK1 SPHK2). Elevated SPHK1 found numerous cancer types shown to contribute survival, chemotherapeutic resistance malignancy. However, its role large granular Natural Killer (NK) lymphocyte (LGL) leukemia not investigated. Here, we examine LGL leukemia. We that overexpressed peripheral...
To further characterize the selectivity, mechanism-of-action and therapeutic efficacy of novel small molecule inhibitor, SKI-178.Using state-of-the-art Cellular Thermal Shift Assay (CETSA) technique to detect "direct target engagement" proteins intact cells, in vitro vivo assays, pharmacological assays multiple mouse models acute myeloid leukemia (AML).Herein, we demonstrate that SKI-178 directly engages both Sphingosine Kinase 1 2. We also present evidence that, addition its actions as a...
Ca<sup>2+</sup> signaling plays an important role in endothelial cell (EC) functions including the regulation of barrier integrity. Recently, endogenous lipid derivative, sphingosine-1-phosphate (S1P), has emerged as modulator EC function. We investigated endogenously generated S1P metabolism and function human umbilical cells (HUVECs) stimulated by thrombin, histamine, or other agonists. Barrier was assessed dextran diffusion through HUVEC monolayers, transients were measured using a...
Meprin A and B are highly regulated, secreted cellsurface homo heterooligomeric enzymes. Meprins abundantly expressed in kidney intestine. The multidomain α β subunits have high sequence identity, however they very different substrate specificities, oligomerization potentials differentially regulated. Here we describe that meprin subunit activities modulated differently by physicochemical factors. Homooligomeric had an acidic pH optimum. low protonation indicated the existence of at least...
Agents that induce immunogenic cell death (ICD) alter the cellular localization of calreticulin (CRT), causing it to become surface–exposed within plasma membrane lipid raft microdomain [cell CRT (ectoCRT)] where serves as a damage associated-molecular pattern elicits an antitumor immune response. We have identified sphingolipid metabolic pathway integral component process ectoCRT exposure. Inhibition sphingosine kinases (SphKs) enhances mitoxantrone-induced production hallmarks ICD,...
The recently renewed interest in scientific rigor and reproducibility is of critical importance for both scientists developing new targeted small-molecule inhibitors those employing these molecule cellular studies, alike. While off-target effects are commonly considered as limitations any given inhibitor, the ability a compound to distinguish between enzyme isoforms often neglected when compounds studies. To call attention this issue, we have compared results an assay "direct target...
The meprin alpha subunit, a multidomain metalloproteinase, is synthesized as type I membrane protein and proteolytically cleaved during biosynthesis in the endoplasmic reticulum (ER), consequently losing its attachment COOH-terminal domains. subunit secreted disulfide-linked dimer that forms higher oligomers. By contrast, evolutionarily related beta retains domains travels to plasma integral dimer. Deletion of unique 56-amino acid inserted domain (the domain) prevents proteolytic processing...
We recently identified the sphingosine kinases (SphK1/2) as key intracellular regulators of immunogenic cell death (ICD) in colorectal cancer (CRC) cells. To better understand mechanism by which SphK inhibition enhances ICD, we focused on signaling pathways leading to surface exposure calreticulin (ectoCRT). Herein, demonstrate that ABT-263 and AZD-5991, inhibitors Bcl-2/Bcl-XL Mcl-1, respectively, induce production ectoCRT, indicative ICD. Inhibition SphK1 significantly enhanced...