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Article ; Online: Raft platforms highly enriched in cholesterol: major scaffolds for IL-6 signalling assembly with implications in inflammation and cancer.

Mollinedo, Faustino

2022 Volume 289, Issue 19, Page(s) 5891–5894

Abstract: Interleukin-6 (IL-6) is a pleiotropic cytokine with complex and major roles in inflammation, which could be linked to the different ways IL-6 signals at the plasma membrane. In this issue of FEBS Journal, Woo and co-workers present evidence for the ... ...

Abstract	Interleukin-6 (IL-6) is a pleiotropic cytokine with complex and major roles in inflammation, which could be linked to the different ways IL-6 signals at the plasma membrane. In this issue of FEBS Journal, Woo and co-workers present evidence for the involvement of Eps15 homology domain-containing protein 1 (EHD1)-mediated lipid raft platforms, highly enriched in cholesterol, in the IL-6 signalling pathway. Because of the strong connection between IL-6, inflammation and cancer, one implication of this report is that agents or approaches targeting cholesterol-rich raft platforms may assist the development of novel strategies to treat inflammatory and malignant diseases. Comment on: https://doi.org/10.1111/febs.16458.
MeSH term(s)	Cholesterol/metabolism ; Cytokines/metabolism ; Humans ; Inflammation/metabolism ; Interleukin-6/genetics ; Interleukin-6/metabolism ; Membrane Microdomains/metabolism ; Neoplasms/pathology ; Vesicular Transport Proteins/metabolism
Chemical Substances	Cytokines ; EHD1 protein, human ; Interleukin-6 ; Vesicular Transport Proteins ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2022-06-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.16547
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Zs.A 260: Show issues

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Article ; Online: Neutrophil Degranulation, Plasticity, and Cancer Metastasis.

Mollinedo, Faustino

Trends in immunology

2019 Volume 40, Issue 3, Page(s) 228–242

Abstract: Neutrophils are the first responders to inflammation and infection. Recently, an elevated neutrophil-to-lymphocyte ratio has generally become a prognostic indicator of poor overall survival in cancer. Accordingly, heterogeneous ill-defined neutrophil- ... ...

Abstract	Neutrophils are the first responders to inflammation and infection. Recently, an elevated neutrophil-to-lymphocyte ratio has generally become a prognostic indicator of poor overall survival in cancer. Accordingly, heterogeneous ill-defined neutrophil-like populations have been increasingly recognized as important players in cancer development. In addition, neutrophil granule proteins released upon cell activation have been associated with tumor progression; this differential granule mobilization may allow neutrophils - and possibly associated cancer cells - to leave the bloodstream and enter inflamed/infected tissues. This review discusses and proposes how granule mobilization may facilitate neutrophil-mediated transport of cancer cells into different tissues as well as leading to different cellular phenotypes that underlie remarkable neutrophil plasticity. This concept might inform novel neutrophil-centered approaches to putative cancer therapies.
MeSH term(s)	Animals ; Carcinogenesis ; Cell Degranulation ; Cell Movement ; Cell Plasticity ; Humans ; Mice ; Neoplasm Metastasis ; Neoplasms/immunology ; Neutrophils/immunology
Language	English
Publishing date	2019-02-15
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2036831-8
ISSN	1471-4981 ; 1471-4906
ISSN (online)	1471-4981
ISSN	1471-4906
DOI	10.1016/j.it.2019.01.006
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Zs.A 1601: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 2: Show issues

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Article ; Online: Clusters of apoptotic signaling molecule-enriched rafts, CASMERs: membrane platforms for protein assembly in Fas/CD95 signaling and targets in cancer therapy.

Mollinedo, Faustino / Gajate, Consuelo

Biochemical Society transactions

2022 Volume 50, Issue 3, Page(s) 1105–1118

Abstract: Mammalian cells show the ability to commit suicide through the activation of death receptors at the cell surface. Death receptors, among which Fas/CD95 is one of their most representative members, lack enzymatic activity, and depend on protein-protein ... ...

Abstract	Mammalian cells show the ability to commit suicide through the activation of death receptors at the cell surface. Death receptors, among which Fas/CD95 is one of their most representative members, lack enzymatic activity, and depend on protein-protein interactions to signal apoptosis. Fas/CD95 death receptor-mediated apoptosis requires the formation of the so-called death-inducing signaling complex (DISC), bringing together Fas/CD95, Fas-associated death domain-containing protein and procaspase-8. In the last two decades, cholesterol-rich lipid raft platforms have emerged as scaffolds where Fas/CD95 can be recruited and clustered. The co-clustering of Fas/CD95 and rafts facilitates DISC formation, bringing procaspase-8 molecules to be bunched together in a limited membrane region, and leading to their autoproteolytic activation by oligomerization. Lipid raft platforms serve as a specific region for the clustering of Fas/CD95 and DISC, as well as for the recruitment of additional downstream signaling molecules, thus forming the so-called cluster of apoptotic signaling molecule-enriched rafts, or CASMER. These raft/CASMER structures float in the membrane like icebergs, in which the larger portion lies inside the cell and communicates with other subcellular structures to facilitate apoptotic signal transmission. This allows an efficient spatiotemporal compartmentalization of apoptosis signaling machinery during the triggering of cell death. This concept of proapoptotic raft platforms as a basic chemical-biological structure in the regulation of cell death has wide-ranging implications in human biology and disease, as well as in cancer therapy. Here, we discuss how these raft-centered proapoptotic hubs operate as a major linchpin for apoptosis signaling and as a promising target in cancer therapy.
MeSH term(s)	Animals ; Apoptosis ; Caspase 8/metabolism ; Humans ; Mammals/metabolism ; Membrane Microdomains ; Neoplasms/metabolism ; fas Receptor/metabolism
Chemical Substances	fas Receptor ; Caspase 8 (EC 3.4.22.-)
Language	English
Publishing date	2022-05-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/BST20211115
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Zs.A 944: Show issues

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Article ; Online: Antitumor activity of alkylphospholipid edelfosine in prostate cancer models and endoplasmic reticulum targeting.

Dakir, El-Habib / Gajate, Consuelo / Mollinedo, Faustino

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2023 Volume 167, Page(s) 115436

Abstract: Prostate cancer is the second most frequent cancer and the fifth leading cause of cancer death among men worldwide. While the five-year survival in local and regional prostate cancer is higher than 99%, it falls to about 28% in advanced metastatic ... ...

Abstract	Prostate cancer is the second most frequent cancer and the fifth leading cause of cancer death among men worldwide. While the five-year survival in local and regional prostate cancer is higher than 99%, it falls to about 28% in advanced metastatic prostate cancer. The ether lipid edelfosine is considered the prototype of a family of promising antitumor drugs collectively named as alkylphospholipid analogs. Here, we found that edelfosine was the most potent alkylphospholipid analog in inducing apoptosis in three different human prostate cancer cell lines (LNCaP, PC3, and DU145) with distinct androgen dependency, and differing in tumor suppressor phosphatase and tensin homolog (PTEN) and p53 status. Edelfosine accumulated in the endoplasmic reticulum of prostate cancer cells, leading to endoplasmic reticulum stress and cell death in the three prostate cancer cells. Inhibition of autophagy potentiated the pro-apoptotic activity of edelfosine in LNCaP and PC3 cells, where autophagy was induced as a survival response. Edelfosine induced a slight and transient inhibition of AKT in PTEN-negative LNCaP and PC3 cells, but not in PTEN-positive DU145 cells. Daily oral administration of edelfosine in murine prostate restricted AKT kinase transgenic mice, expressing active AKT in a prostate-specific manner, and in a DU145 xenograft mouse model resulted in significant tumor regression and apoptosis in tumor cells. Taken together, these results show a significant in vitro and in vivo antitumor activity of edelfosine against prostate cancer, and highlight the endoplasmic reticulum as a novel and promising therapeutic target in prostate cancer.
Language	English
Publishing date	2023-09-08
Publishing country	France
Document type	Journal Article
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2023.115436
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Ud II Zs.198: Show issues

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Article: Mitochondrial Targeting Involving Cholesterol-Rich Lipid Rafts in the Mechanism of Action of the Antitumor Ether Lipid and Alkylphospholipid Analog Edelfosine.

Mollinedo, Faustino / Gajate, Consuelo

Pharmaceutics

2021 Volume 13, Issue 5

Abstract: The ether lipid edelfosine induces apoptosis selectively in tumor cells and is the prototypic molecule of a family of synthetic antitumor compounds collectively known as alkylphospholipid analogs. Cumulative evidence shows that edelfosine interacts with ... ...

Abstract	The ether lipid edelfosine induces apoptosis selectively in tumor cells and is the prototypic molecule of a family of synthetic antitumor compounds collectively known as alkylphospholipid analogs. Cumulative evidence shows that edelfosine interacts with cholesterol-rich lipid rafts, endoplasmic reticulum (ER) and mitochondria. Edelfosine induces apoptosis in a number of hematological cancer cells by recruiting death receptors and downstream apoptotic signaling into lipid rafts, whereas it promotes apoptosis in solid tumor cells through an ER stress response. Edelfosine-induced apoptosis, mediated by lipid rafts and/or ER, requires the involvement of a mitochondrial-dependent step to eventually elicit cell death, leading to the loss of mitochondrial membrane potential, cytochrome
Language	English
Publishing date	2021-05-20
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics13050763
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Article: Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer.

Mollinedo, Faustino / Gajate, Consuelo

Cancers

2021 Volume 13, Issue 16

Abstract: Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, shows a dismal and grim overall prognosis and survival rate, which have remained virtually unchanged for over half a century. PDAC is the most lethal of all cancers, ... ...

Abstract	Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, shows a dismal and grim overall prognosis and survival rate, which have remained virtually unchanged for over half a century. PDAC is the most lethal of all cancers, with the highest mortality-to-incidence ratio. PDAC responds poorly to current therapies and remains an incurable malignancy. Therefore, novel therapeutic targets and drugs are urgently needed for pancreatic cancer treatment. Selective induction of apoptosis in cancer cells is an appealing approach in cancer therapy. Apoptotic cell death is highly regulated by different signaling routes that involve a variety of subcellular organelles. Endoplasmic reticulum (ER) stress acts as a double-edged sword at the interface of cell survival and death. Pancreatic cells exhibit high hormone and enzyme secretory functions, and thereby show a highly developed ER. Thus, pancreatic cancer cells display a prominent ER. Solid tumors have to cope with adverse situations in which hypoxia, lack of certain nutrients, and the action of certain antitumor agents lead to a complex interplay and crosstalk between ER stress and autophagy-the latter acting as an adaptive survival response. ER stress also mediates cell death induced by a number of anticancer drugs and experimental conditions, highlighting the pivotal role of ER stress in modulating cell fate. The alkylphospholipid analog prototype edelfosine is selectively taken up by tumor cells, accumulates in the ER of a number of human solid tumor cells-including pancreatic cancer cells-and promotes apoptosis through a persistent ER-stress-mediated mechanism both in vitro and in vivo. Here, we discuss and propose that direct ER targeting may be a promising approach in the therapy of pancreatic cancer, opening up a new avenue for the treatment of this currently incurable and deadly cancer. Furthermore, because autophagy acts as a cytoprotective response to ER stress, potentiation of the triggering of a persistent ER response by combination therapy, together with the use of autophagy blockers, could improve the current gloomy expectations for finding a cure for this type of cancer.
Language	English
Publishing date	2021-08-19
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13164173
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Article: Novel therapeutic approaches for pancreatic cancer by combined targeting of RAF→MEK→ERK signaling and autophagy survival response.

Mollinedo, Faustino / Gajate, Consuelo

Annals of translational medicine

2019 Volume 7, Issue Suppl 3, Page(s) S153

Language	English
Publishing date	2019-09-25
Publishing country	China
Document type	Editorial ; Comment
ZDB-ID	2893931-1
ISSN	2305-5847 ; 2305-5839
ISSN (online)	2305-5847
ISSN	2305-5839
DOI	10.21037/atm.2019.06.40
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Article ; Online: Lipid Raft Isolation by Sucrose Gradient Centrifugation and Visualization of Raft-Located Proteins by Fluorescence Microscopy: The Use of Combined Techniques to Assess Fas/CD95 Location in Rafts During Apoptosis Triggering.

Gajate, Consuelo / Mollinedo, Faustino

Methods in molecular biology (Clifton, N.J.)

2020 Volume 2187, Page(s) 147–186

Abstract: Lipid rafts are heterogeneous membrane domains enriched in cholesterol, sphingolipids, and gangliosides that serve as sorting platforms to compartmentalize and modulate signaling pathways. Death receptors and downstream signaling molecules have been ... ...

Abstract	Lipid rafts are heterogeneous membrane domains enriched in cholesterol, sphingolipids, and gangliosides that serve as sorting platforms to compartmentalize and modulate signaling pathways. Death receptors and downstream signaling molecules have been reported to be recruited into these raft domains during the triggering of apoptosis. Here, we provide two protocols that support the presence of Fas/CD95 in lipid rafts during apoptosis, involving lipid raft isolation and confocal microscopy techniques. A detailed protocol is provided for the isolation of lipid rafts, by taking advantage of their resistance to Triton X-100 solubilization at 4 °C, followed by subsequent sucrose gradient centrifugation and analysis of the protein composition of the different gradient fractions by Western blotting. In addition, we also provide a detailed protocol for the visualization of the coclustering of Fas/CD95 death receptor and lipid rafts, as assessed by using anti-Fas/CD95 antibodies and fluorescent dye-conjugated cholera toxin B subunit that binds to ganglioside GM1, a main component of lipid rafts, by immunofluorescence and confocal microscopy. These protocols can be extended to any protein of interest to be analyzed for its association to lipid rafts.
MeSH term(s)	Apoptosis/physiology ; Cell Line, Tumor ; Centrifugation/methods ; Cholera Toxin/metabolism ; G(M1) Ganglioside/metabolism ; Humans ; Membrane Lipids/chemistry ; Membrane Lipids/metabolism ; Membrane Microdomains/chemistry ; Membrane Microdomains/metabolism ; Microscopy, Fluorescence/methods ; Octoxynol/chemistry ; Protein Binding/physiology ; Signal Transduction/physiology ; Sucrose/chemistry ; fas Receptor/chemistry ; fas Receptor/metabolism
Chemical Substances	Membrane Lipids ; fas Receptor ; G(M1) Ganglioside (37758-47-7) ; Sucrose (57-50-1) ; Octoxynol (9002-93-1) ; Cholera Toxin (9012-63-9)
Language	English
Publishing date	2020-08-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-0814-2_9
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Article ; Online: Lipid rafts as signaling hubs in cancer cell survival/death and invasion: implications in tumor progression and therapy: Thematic Review Series: Biology of Lipid Rafts.

Mollinedo, Faustino / Gajate, Consuelo

Journal of lipid research

2020 Volume 61, Issue 5, Page(s) 611–635

Abstract: Cholesterol/sphingolipid-rich membrane domains, known as lipid rafts or membrane rafts, play a critical role in the compartmentalization of signaling pathways. Physical segregation of proteins in lipid rafts may modulate the accessibility of proteins to ... ...

Abstract	Cholesterol/sphingolipid-rich membrane domains, known as lipid rafts or membrane rafts, play a critical role in the compartmentalization of signaling pathways. Physical segregation of proteins in lipid rafts may modulate the accessibility of proteins to regulatory or effector molecules. Thus, lipid rafts serve as sorting platforms and hubs for signal transduction proteins. Cancer cells contain higher levels of intracellular cholesterol and lipid rafts than their normal non-tumorigenic counterparts. Many signal transduction processes involved in cancer development (insulin-like growth factor system and phosphatidylinositol 3-kinase-AKT) and metastasis [cluster of differentiation (CD)44] are dependent on or modulated by lipid rafts. Additional proteins playing an important role in several malignant cancers (e.g., transmembrane glycoprotein mucin 1) are also being detected in association with lipid rafts, suggesting a major role of lipid rafts in tumor progression. Conversely, lipid rafts also serve as scaffolds for the recruitment and clustering of Fas/CD95 death receptors and downstream signaling molecules leading to cell death-promoting raft platforms. The partition of death receptors and downstream signaling molecules in aggregated lipid rafts has led to the formation of the so-called cluster of apoptotic signaling molecule-enriched rafts, or CASMER, which leads to apoptosis amplification and can be pharmacologically modulated. These death-promoting rafts can be viewed as a linchpin from which apoptotic signals are launched. In this review, we discuss the involvement of lipid rafts in major signaling processes in cancer cells, including cell survival, cell death, and metastasis, and we consider the potential of lipid raft modulation as a promising target in cancer therapy.
MeSH term(s)	Animals ; Cell Death ; Cell Survival ; Disease Progression ; Humans ; Membrane Microdomains/pathology ; Neoplasm Invasiveness ; Neoplasms/pathology ; Neoplasms/therapy ; Signal Transduction
Language	English
Publishing date	2020-11-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80154-9
ISSN	1539-7262 ; 0022-2275
ISSN (online)	1539-7262
ISSN	0022-2275
DOI	10.1194/jlr.TR119000439
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Zs.A 175: Show issues

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Article ; Online: Editorial: Antitumor alkylphospholipid analogs: a promising and growing family of synthetic cell membrane-targeting molecules for cancer treatment).

Mollinedo, Faustino

Anti-cancer agents in medicinal chemistry

2014 Volume 14, Issue 4, Page(s) 495–498

MeSH term(s)	Animals ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cell Membrane/metabolism ; Humans ; Molecular Targeted Therapy ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Neoplasms/ultrastructure ; Plasmalogens/chemistry ; Plasmalogens/pharmacology ; Plasmalogens/therapeutic use
Chemical Substances	Antineoplastic Agents ; Plasmalogens
Language	English
Publishing date	2014-01-16
Publishing country	Netherlands
Document type	Editorial ; Introductory Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2217610-X
ISSN	1875-5992 ; 1871-5206
ISSN (online)	1875-5992
ISSN	1871-5206
DOI	10.2174/1871520614999140313160011
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Zs.A 5583: Show issues

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