A5055590804- Metabolism, Diabetes, and Cancer
- Caveolin-1 and cellular processes
- interferon and immune responses
- Autophagy in Disease and Therapy
- Alzheimer's disease research and treatments
- Immune cells in cancer
- Erythrocyte Function and Pathophysiology
- Immune Cell Function and Interaction
- Cancer Immunotherapy and Biomarkers
- Cholinesterase and Neurodegenerative Diseases
- Ion Transport and Channel Regulation
- Ubiquitin and proteasome pathways
- Adipose Tissue and Metabolism
- Pancreatic function and diabetes
- Drug Transport and Resistance Mechanisms
- Animal Genetics and Reproduction
- Protein Kinase Regulation and GTPase Signaling
- Adenosine and Purinergic Signaling
- Lipid metabolism and biosynthesis
- Diet, Metabolism, and Disease
- Ferroptosis and cancer prognosis
- Inflammasome and immune disorders
- Cytokine Signaling Pathways and Interactions
- FOXO transcription factor regulation
- Signaling Pathways in Disease
Karolinska Institutet
2020-2024
Sprint Bioscience (Sweden)
2018-2024
AstraZeneca (United Kingdom)
2012
AstraZeneca (Sweden)
2011-2012
Linköping University
1994-2001
One of the major challenges limiting efficacy anti-PD-1/PD-L1 therapy in nonresponding patients is failure T cells to penetrate tumor microenvironment. We showed that genetic or pharmacological inhibition Vps34 kinase activity using SB02024 SAR405 (Vps34i) decreased growth and improved mice survival multiple models by inducing an infiltration NK, CD8+, CD4+ effector melanoma CRC tumors. Such resulted establishment a cell-inflamed microenvironment, characterized up-regulation pro-inflammatory...
The insulin receptor is a transmembrane protein of the plasma membrane, where it recognizes extracellular and transmits signals into cellular signaling network. We report that receptors are localized signal in caveolae microdomains adipocyte membrane. Immunogold electron microscopy immunofluorescence show restricted to colocalized with caveolin over Insulin was enriched caveolae-enriched fraction By extraction β-cyclodextrin or destruction cholesterol oxidase, reduction attenuated...
Insulin exerts its cellular control through receptor binding in caveolae plasmalemma of target cells (Gustavsson, J., Parpal, S., Karlsson, M., Ramsing, C., Thorn, H., Borg, Lindroth, Peterson, K. Magnusson, K.-E., and Strålfors, P. (1999) FASEB. J. 13, 1961–1971). We now report that a progressive cholesterol depletion 3T3-L1 adipocytes with β-cyclodextrin gradually destroyed structures concomitantly attenuated insulin stimulation glucose transport, effect making insulin-resistant. access to...
Resistance to chemotherapy is a challenging problem for treatment of cancer patients and autophagy has been shown mediate development resistance. In this study we systematically screened library 306 known anti-cancer drugs their ability induce using cell-based assay. 114 the were classified as inducers; 16 drugs, cytotoxicity was potentiated by siRNA-mediated knock-down Atg7 Vps34. These further evaluated in breast cell lines induction, two tyrosine kinase inhibitors, Sunitinib Erlotinib,...
Insulin-stimulated glucose uptake in muscle and adipose tissue is the result of translocation insulin-regulated transporters (GLUT4) from intracellular vesicles to plasma membrane. Here we report that GLUT4 membrane 3T3-L1 adipocytes were located predominantly caveolae invaginations: by immunogold electron microscopy membranes, 88% localized structures this distribution within was not affected insulin. By immunofluorescence microscopy, a major part GLUT 4 colocalized with caveolin. The total...
An immunosuppressive tumor microenvironment promotes growth and is one of the main factors limiting response to cancer immunotherapy. We have previously reported that inhibition vacuolar protein sorting 34 (VPS34), a crucial lipid kinase in autophagy/endosomal trafficking pathway, decreases several models, increases infiltration immune cells sensitizes tumors anti-programmed cell death 1/programmed 1 ligand therapy by upregulation C-C motif chemokine 5 (CCL5) C-X-C 10 (CXCL10) chemokines....
γ-Secretase inhibition represents a major therapeutic strategy for lowering amyloid β (Aβ) peptide production in Alzheimer's disease (AD). Progress toward clinical use of γ-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related impairment Notch signaling. The inhibitor MRK-560 an exception as it is largely tolerable vivo despite displaying only small selectivity between Aβ and signaling vitro . In exploring the molecular basis observed...
A phosphooligosaccharide has been proposed as a second messenger of insulin. It is believed to be structurally related the carbohydrate moiety phosphatidylinositol glycan anchors many cell surface proteins. Herein we demonstrate that [32]phosphate in freshly isolated adipocytes and [3H]galactose cultured hepatoma cells (H4IIE) labeled same set three different glycolipids. With all three, radiolabel was made water soluble by phosphatidylinositol(glycan)-specific phospholipase C or D catalyzed...
The involvement of Raf-1 kinase in the insulin signal transduction chain leading to control cell proliferation was studied H4IIE rat hepatoma line by inhibiting expression with antisense oligodeoxyribonucleotide directed against mRNA. Antisense oligonucleotide found reduce (at 2 microM) or completely block 15 stimulation DNA synthesis, measured as thymidine incorporation. residual synthesis seen absence also inhibited oligonucleotide.
Abstract Novel approaches to reduce tumor immunosuppression and improve responses anti-cancer immunotherapies based on immune-checkpoint inhibitors are needed. Emerging evidence demonstrates that autophagy inhibition enhances anti-tumor immunity by cell-intrinsic extrinsic mechanisms. Recently, we reported pharmacological of VPS34 (PIK3C3), a lipid kinase regulating initiation, decreases growth the efficacy anti-PD-1/PD-L1 therapy in melanoma colorectal cancer mouse models. This effect was...
Processing of amyloid ß-precursor protein (APP) into the Alzheimer related ß-peptide (Aß) is a proteolytic event mediated by γ-secretase complex. γ-Secretase cleaves APP in two different sites, γ-site and ε-site, generating Aß-peptides lengths intracellular domain. The complex processes several type I membrane bound proteins among them Notch receptor. an important signalling molecule many tissues organs during development but also adulthood. similar pattern as APP, Nß peptide (S4-cleavage)...