scholarly journals The Necroptosis Effector MLKL drives Small Extracellular Vesicle Release and Tumour Growth in Glioblastoma

2021 ◽  
Author(s):  
Gwennan André-Grégoire ◽  
Tiphaine Douanne ◽  
An Thys ◽  
Clément Maghe ◽  
Kathryn Jacobs ◽  
...  
Keyword(s):  
Tumour Growth ◽  
Tumour Progression ◽  
Therapeutic Option ◽  
Extracellular Vesicle ◽  
Endosomal Trafficking ◽  
Tumour Burden ◽  
Vesicle Release ◽  
Constitutive Secretion

AbstractExtracellular vesicles (EVs) are lipid-based nano-sized particles that convey biological material from donor to recipient cells. They play key roles in tumour progression, notably in glioblastoma in which the subpopulation of Glioblastoma Stem-like Cells (GSCs) might represent a meaningful source of tumour-derived EVs. However, the mechanisms involved in the production and release of EVs by GSCs are still poorly understood. Here, we report the identification of MLKL, a crucial effector of cell death by necroptosis, as a regulator of the constitutive secretion of small EVs from GSCs. The targeting of MLKL by genetic, protein depletion or chemical approaches alters endosomal trafficking and EV release and reduces GSC expansion in vitro. This function ascribed to MLKL appears independent of its role during necroptosis. In vivo, pharmacological inhibition of MLKL triggers a reduction of both the tumour burden in xenografted mice and of the level of plasmatic EVs. This work reinforces the idea of a non-deadly role for MLKL in endosomal trafficking and suggests that interfering with EV biogenesis is a promising therapeutic option to sensitize glioblastoma cells to death.

scholarly journals Extracellular vesicle budding is inhibited by redundant regulators of TAT-5 flippase localization and phospholipid asymmetry

2018 ◽  
Vol 115 (6) ◽  
pp. E1127-E1136 ◽  
Author(s):  
Katharina B. Beer ◽  
Jennifer Rivas-Castillo ◽  
Kenneth Kuhn ◽  
Gholamreza Fazeli ◽  
Birgit Karmann ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Extracellular Vesicle ◽  
Endosomal Trafficking ◽  
Vesicle Budding ◽  
Sorting Nexins ◽  
Dnaj Protein ◽  
Membrane Budding ◽  
Pleiotropic Functions

Cells release extracellular vesicles (EVs) that mediate intercellular communication and repair damaged membranes. Despite the pleiotropic functions of EVs in vitro, their in vivo function is debated, largely because it is unclear how to induce or inhibit their formation. In particular, the mechanisms of EV release by plasma membrane budding or ectocytosis are poorly understood. We previously showed that TAT-5 phospholipid flippase activity maintains the asymmetric localization of the lipid phosphatidylethanolamine (PE) in the plasma membrane and inhibits EV budding by ectocytosis in Caenorhabditis elegans. However, no proteins that inhibit ectocytosis upstream of TAT-5 were known. Here, we identify TAT-5 regulators associated with retrograde endosomal recycling: PI3Kinase VPS-34, Beclin1 homolog BEC-1, DnaJ protein RME-8, and the uncharacterized Dopey homolog PAD-1. PI3Kinase, RME-8, and semiredundant sorting nexins are required for the plasma membrane localization of TAT-5, which is important to maintain PE asymmetry and inhibit EV release. PAD-1 does not directly regulate TAT-5 localization, but is required for the lipid flipping activity of TAT-5. PAD-1 also has roles in endosomal trafficking with the GEF-like protein MON-2, which regulates PE asymmetry and EV release redundantly with sorting nexins independent of the core retromer. Thus, in addition to uncovering redundant intracellular trafficking pathways, our study identifies additional proteins that regulate EV release. This work pinpoints TAT-5 and PE as key regulators of plasma membrane budding, further supporting the model that PE externalization drives ectocytosis.

scholarly journals Pharmacological inhibition of Mint3 attenuates tumour growth, metastasis, and endotoxic shock

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Takeharu Sakamoto ◽  
Yuya Fukui ◽  
Yasumitsu Kondoh ◽  
Kaori Honda ◽  
Takeshi Shimizu ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Cancer Cells ◽  
Transcriptional Activity ◽  
Tumour Growth ◽  
Inflammatory Diseases ◽  
Therapeutic Option ◽  
Endotoxic Shock ◽  
Hypoxia Inducible Factor

AbstractHypoxia-inducible factor-1 (HIF-1) plays essential roles in human diseases, though its central role in oxygen homoeostasis hinders the development of direct HIF-1-targeted pharmacological approaches. Here, we surveyed small-molecule compounds that efficiently inhibit the transcriptional activity of HIF-1 without affecting body homoeostasis. We focused on Mint3, which activates HIF-1 transcriptional activity in limited types of cells, such as cancer cells and macrophages, by suppressing the factor inhibiting HIF-1 (FIH-1). We identified naphthofluorescein, which inhibited the Mint3–FIH-1 interaction in vitro and suppressed Mint3-dependent HIF-1 activity and glycolysis in cancer cells and macrophages without evidence of cytotoxicity in vitro. In vivo naphthofluorescein administration suppressed tumour growth and metastasis without adverse effects, similar to the genetic depletion of Mint3. Naphthofluorescein attenuated inflammatory cytokine production and endotoxic shock in mice. Thus, Mint3 inhibitors may present a new targeted therapeutic option for cancer and inflammatory diseases by avoiding severe adverse effects.

Exploiting Anti-Inflammation Effects of Flavonoids in Chronic Inflammatory Diseases

2020 ◽  
Vol 26 (22) ◽  
pp. 2610-2619 ◽  
Author(s):  
Tarique Hussain ◽  
Ghulam Murtaza ◽  
Huansheng Yang ◽  
Muhammad S. Kalhoro ◽  
Dildar H. Kalhoro
Keyword(s):  
Oxidative Stress ◽  
Chronic Diseases ◽  
Inflammatory Diseases ◽  
Therapeutic Option ◽  
Cellular Level ◽  
Antiinflammatory Drugs ◽  
Suitable Alternative ◽  
Chronic Inflammatory Diseases

Background: Inflammation is a complex response of the host defense system to different internal and external stimuli. It is believed that persistent inflammation may lead to chronic inflammatory diseases such as, inflammatory bowel disease, neurological and cardiovascular diseases. Oxidative stress is the main factor responsible for the augmentation of inflammation via various molecular pathways. Therefore, alleviating oxidative stress is effective a therapeutic option against chronic inflammatory diseases. Methods: This review article extends the knowledge of the regulatory mechanisms of flavonoids targeting inflammatory pathways in chronic diseases, which would be the best approach for the development of suitable therapeutic agents against chronic diseases. Results: Since the inflammatory response is initiated by numerous signaling molecules like NF-κB, MAPK, and Arachidonic acid pathways, their encountering function can be evaluated with the activation of Nrf2 pathway, a promising approach to inhibit/prevent chronic inflammatory diseases by flavonoids. Over the last few decades, flavonoids drew much attention as a potent alternative therapeutic agent. Recent clinical evidence has shown significant impacts of flavonoids on chronic diseases in different in-vivo and in-vitro models. Conclusion: Flavonoid compounds can interact with chronic inflammatory diseases at the cellular level and modulate the response of protein pathways. A promising approach is needed to overlook suitable alternative compounds providing more therapeutic efficacy and exerting fewer side effects than commercially available antiinflammatory drugs.

Ethanolic Extract of Algerian Propolis and Galangin Decreased Murine Melanoma Tumor Progression in Mice

2016 ◽  
Vol 16 (9) ◽  
pp. 1172-1183 ◽  
Author(s):  
Lamia Benguedouar ◽  
Mesbah Lahouel ◽  
Sophie C. Gangloff ◽  
Anne Durlach ◽  
Florent Grange ◽  
...  
Keyword(s):  
Tumour Growth ◽  
Tumour Progression ◽  
Ethanolic Extract ◽  
Complementary Therapy ◽  
Melanoma Cells ◽  
Biological Properties ◽  
Therapeutic Treatment ◽  
Melanoma Tumor ◽  
Ki 67

Melanoma is the more dangerous skin cancer, and metastatic melanoma still carries poor prognosis. Despite recent therapeutic advances, prolonged survival remains rare and research is still required. Propolis extracts from many countries have attracted a great deal of attention for their biological properties. We here investigated the ability of an ethanolic extract of Algerian propolis (EEP) to control melanoma tumour growth when given to mice bearing B16F1melanoma tumour either as preventive or as therapeutic treatment. EEP given after tumour occurrence increased mice survival (+30%) and reduced tumour growth (-75%). This was associated with a decrease of the Mitotic Index (-75%) and of Ki-67 (-50%) expression. When given either before or both before and after tumour occurrence, EEP reduced tumour growth but without prolonging mice life. Isolation of B16F1 melanoma cells from resected tumour showed that preventive and curative EEP treatments reduced invasiveness by 55% and 40% respectively compared to control. Galangin, one of the most abundant flavonoids in propolis, significantly reduced the number of melanoma cells in vitro and induced autophagy/apoptosis dose dependently. In conclusion, we showed that EEP reduced melanoma tumour progression/dissemination and could extend mice lifespan when used as therapeutic treatment. Then, EEP may help patients with melanoma when used as a complementary therapy to classical treatment for which autophagy is not contraindicated.

scholarly journals Operative ubiquitin-specific protease 22 deubiquitination confers a more invasive phenotype to cholangiocarcinoma

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Yu Tian ◽  
Bo Tang ◽  
Chengye Wang ◽  
Yan Wang ◽  
Jiakai Mao ◽  
...  
Keyword(s):  
Tumour Growth ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Sirtuin 1 ◽  
Mesenchymal Transition ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Paired Tumour

AbstractOncogenic ubiquitin-specific protease 22 (USP22) is implicated in a variety of tumours; however, evidence of its role and underlying molecular mechanisms in cholangiocarcinoma (CCA) development remains unknown. We collected paired tumour and adjacent non-tumour tissues from 57 intrahepatic CCA (iCCA) patients and evaluated levels of the USP22 gene and protein by qPCR and immunohistochemistry. Both the mRNA and protein were significantly upregulated, correlated with the malignant invasion and worse OS of iCCA. In cell cultures, USP22 overexpression increased CCA cell proliferation and mobility, and induced epithelial-to-mesenchymal transition (EMT). Upon an interaction, USP22 deubiquitinated and stabilized sirtuin-1 (SIRT1), in conjunction with Akt/ERK activation. In implantation xenografts, USP22 overexpression stimulated tumour growth and metastasis to the lungs of mice. Conversely, the knockdown by USP22 shRNA attenuated the tumour growth and invasiveness in vitro and in vivo. Furthermore, SIRT1 overexpression reversed the USP22 functional deficiency, while the knockdown acetylated TGF-β-activated kinase 1 (TAK1) and Akt. Our present study defines USP22 as a poor prognostic predictor in iCCA that cooperates with SIRT1 and facilitates tumour development.

scholarly journals TBC-2 Regulates RAB-5/RAB-7-mediated Endosomal Trafficking inCaenorhabditis elegans

2010 ◽  
Vol 21 (13) ◽  
pp. 2285-2296 ◽  
Author(s):  
Laëtitia Chotard ◽  
Ashwini K. Mishra ◽  
Marc-André Sylvain ◽  
Simon Tuck ◽  
David G. Lambright ◽  
...  
Keyword(s):  
Rab Gtpase ◽  
Endosomal Trafficking ◽  
Dependent Manner ◽  
Nucleotide Exchange ◽  
Late Endosomes ◽  
Arginine Finger ◽  
Endosome Maturation ◽  
Hops Complex

During endosome maturation the early endosomal Rab5 GTPase is replaced with the late endosomal Rab7 GTPase. It has been proposed that active Rab5 can recruit and activate Rab7, which in turn could inactivate and remove Rab5. However, many of the Rab5 and Rab7 regulators that mediate endosome maturation are not known. Here, we identify Caenorhabditis elegans TBC-2, a conserved putative Rab GTPase-activating protein (GAP), as a regulator of endosome to lysosome trafficking in several tissues. We show that tbc-2 mutant animals accumulate enormous RAB-7–positive late endosomes in the intestine containing refractile material. RAB-5, RAB-7, and components of the homotypic fusion and vacuole protein sorting (HOPS) complex, a RAB-7 effector/putative guanine nucleotide exchange factor (GEF), are required for the tbc-2(−) intestinal phenotype. Expression of activated RAB-5 Q78L in the intestine phenocopies the tbc-2(−) large late endosome phenotype in a RAB-7 and HOPS complex-dependent manner. TBC-2 requires the catalytic arginine-finger for function in vivo and displays the strongest GAP activity on RAB-5 in vitro. However, TBC-2 colocalizes primarily with RAB-7 on late endosomes and requires RAB-7 for membrane localization. Our data suggest that TBC-2 functions on late endosomes to inactivate RAB-5 during endosome maturation.

scholarly journals Membrane Vesicle Release in Bacteria, Eukaryotes, and Archaea: a Conserved yet Underappreciated Aspect of Microbial Life

2012 ◽  
Vol 80 (6) ◽  
pp. 1948-1957 ◽  
Author(s):  
Brooke L. Deatherage ◽  
Brad T. Cookson
Keyword(s):  
Membrane Vesicle ◽  
Membrane Vesicles ◽  
Outer Membrane Vesicles ◽  
Host Immune System ◽  
Vesicle Release ◽  
Communication Signals ◽  
Microbial Life ◽  
Functional Features

ABSTRACTInteraction of microbes with their environment depends on features of the dynamic microbial surface throughout cell growth and division. Surface modifications, whether used to acquire nutrients, defend against other microbes, or resist the pressures of a host immune system, facilitate adaptation to unique surroundings. The release of bioactive membrane vesicles (MVs) from the cell surface is conserved across microbial life, in bacteria, archaea, fungi, and parasites. MV production occurs not onlyin vitrobut alsoin vivoduring infection, underscoring the influence of these surface organelles in microbial physiology and pathogenesis through delivery of enzymes, toxins, communication signals, and antigens recognized by the innate and adaptive immune systems. Derived from a variety of organisms that span kingdoms of life and called by several names (membrane vesicles, outer membrane vesicles [OMVs], exosomes, shedding microvesicles, etc.), the conserved functions and mechanistic strategies of MV release are similar, including the use of ESCRT proteins and ESCRT protein homologues to facilitate these processes in archaea and eukaryotic microbes. Although forms of MV release by different organisms share similar visual, mechanistic, and functional features, there has been little comparison across microbial life. This underappreciated conservation of vesicle release, and the resulting functional impact throughout the tree of life, explored in this review, stresses the importance of vesicle-mediated processes throughout biology.

STEM-18. STROMAL EXTRACELLULAR VESICLES DRIVE GLIOMA STEM CELL REPROGRAMMING

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi24-vi25
Author(s):  
Lata Adnani ◽  
Brian Meehan ◽  
Jordan Kassouf ◽  
Cristiana Spinelli ◽  
Nadim Tawil ◽  
...  
Keyword(s):  
Molecular Subtype ◽  
Extracellular Vesicle ◽  
Host Cells ◽  
Tumour Mass ◽  
Membrane Structures ◽  
And Function ◽  
Rate Limiting ◽  
The Brain

Abstract Glioblastoma multiforme (GBM) represents the most frequent and lethal form of brain tumors originating from glioma stem cells (GSCs). GBM remains lethal because the rate limiting patho-mechanisms remain poorly understood. In this regard, few limitations involve the diversity 'between' cellular states and the molecular/cellular complexity 'within' the tumour mass. Using cell based- and mouse- models, we explored extracellular vesicle (EV) mediated interactions between cancer and stromal cells impacting phenotypes of GSCs as a function of their molecular subtype. EVs are spherical membrane structures that cells release to expel different molecular cargo (lipids, proteins, RNA, DNA), which can be transported across a distance in the brain and taken up by various ‘recipient’ cells resulting in reprogramming of the recipient cell's content and function. In vivo, GSCs altered their pattern of NOTCH signalling and molecular phenotype as a function of proximity to non-transformed host cells in the brain. In vitro stromal EVs altered GSC sphere forming capacity, proteome and expression of mesenchymal markers. Thus, EV mediated tumour-stromal interactions could represent a biological switch and a novel targeting point in the biology of GBM.

scholarly journals Cardioprotective Effects of Puerarin-V on Isoproterenol-Induced Myocardial Infarction Mice Is Associated with Regulation of PPAR-Υ/NF-κB Pathway

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3322 ◽  
Author(s):  
Xuguang Li ◽  
Tianyi Yuan ◽  
Di Chen ◽  
Yucai Chen ◽  
Shuchan Sun ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Inflammatory Responses ◽  
Therapeutic Option ◽  
Crystal Form ◽  
Human Coronary Artery ◽  
Beneficial Effects ◽  
Ppar Γ ◽  
Cardioprotective Effects

Puerarin is a well-known traditional Chinese medicine which has been used for the treatment of cardiovascular diseases. Recently, a new advantageous crystal form of puerarin, puerarin-V, has been developed. However, the cardioprotective effects of puerarin-V on myocardial infarction (MI) heart failure are still unclear. In this research, we aim to evaluate the cardioprotective effects of puerarin-V on the isoproterenol (ISO)-induced MI mice and elucidate the underlying mechanisms. To induce MI in C57BL/6 mice, ISO was administered at 40 mg/kg subcutaneously every 12 h for three times in total. The mice were randomly divided into nine groups: (1) control; (2) ISO; (3) ISO + puerarin injection; (4–9) ISO + puerarin-V at different doses and timings. After treatment, cardiac function was evaluated by electrocardiogram (ECG), biochemical and histochemical analysis. In vitro inflammatory responses and apoptosis were evaluated in human coronary artery endothelial cells (HCAECs) challenged by lipopolysaccharide (LPS). LPS-induced PPAR-Υ/NF-κB and subsequently activation of cytokines were assessed by the western blot and real-time polymerase chain reaction (PCR). Administration of puerarin-V significantly inhibits the typical ST segment depression compared with that in MI mice. Further, puerarin-V treatment significantly improves ventricular wall infarction, decreases the incidence of mortality, and inhibits the levels of myocardial injury markers. Moreover, puerarin-V treatment reduces the inflammatory milieu in the heart of MI mice, thereby blocking the upregulation of proinflammatory cytokines (TNF-α, IL-1β and IL-6). The beneficial effects of puerarin-V might be associated with the normalization in gene expression of PPAR-Υ and PPAR-Υ/NF-κB /ΙκB-α/ΙΚΚα/β phosphorylation. In the in vitro experiment, treatment with puerarin-V (0.3, 1 and 3 μM) significantly reduces cell death and suppresses the inflammation cytokines expression. Likewise, puerarin-V exhibits similar mechanisms. The cardioprotective effects of puerarin-V treatment on MI mice in the pre + post-ISO group seem to be more prominent compared to those in the post-ISO group. Puerarin-V exerts cardioprotective effects against ISO-induced MI in mice, which may be related to the activation of PPAR-γ and the inhibition of NF-κB signaling in vivo and in vitro. Taken together, our research provides a new therapeutic option for the treatment of MI in clinic.

Sign in / Sign up

Export Citation Format

Share Document