Evolving Diagnostic and Treatment Strategies for Pediatric CNS Tumors: The Impact of Lipid Metabolism.

Pediatric neurological tumors are a heterogeneous group of cancers, many of which carry a poor prognosis and lack a "standard of care" therapy. While they have similar anatomic locations, pediatric neurological tumors harbor specific molecular signatures that distinguish them from adult brain and other neurological cancers. Recent advances through the application of genetics and imaging tools have reshaped the molecular classification and treatment of pediatric neurological tumors, specifically considering the molecular alterations involved.

HCA (2-Hydroxy-Docosahexaenoic Acid) Induces Apoptosis and Endoplasmic Reticulum Stress in Pancreatic Cancer Cells.

Pancreatic cancer has a high mortality rate due to its aggressive nature and high metastatic rate. When coupled to the difficulties in detecting this type of tumor early and the lack of effective treatments, this cancer is currently one of the most important clinical challenges in the field of oncology. Melitherapy is an innovative therapeutic approach that is based on modifying the composition and structure of cell membranes to treat different diseases, including cancers.

Multifaceted Analyses of Isolated Mitochondria Establish the Anticancer Drug 2-Hydroxyoleic Acid as an Inhibitor of Substrate Oxidation and an Activator of Complex IV-Dependent State 3 Respiration.

The synthetic fatty acid 2-hydroxyoleic acid (2OHOA) has been extensively investigated as a cancer therapy mainly based on its regulation of membrane lipid composition and structure, activating various cell fate pathways. We discovered, additionally, that 2OHOA can uncouple oxidative phosphorylation, but this has never been demonstrated mechanistically. Here, we explored the effect of 2OHOA on mitochondria isolated by ultracentrifugation from U118MG glioblastoma cells.

Tri-2-Hydroxyarachidonein Induces Cytocidal Autophagy in Pancreatic Ductal Adenocarcinoma Cancer Cell Models.

Cell proliferation in pancreatic cancer is determined by a complex network of signaling pathways. Despite the extensive understanding of these protein-mediated signaling processes, there are no significant drug discoveries that could considerably improve a patient's survival. However, the recent understanding of lipid-mediated signaling gives a new perspective on the control of the physiological state of pancreatic cells.

Lipids in Pathophysiology and Development of the Membrane Lipid Therapy: New Bioactive Lipids.

Membranes are mainly composed of a lipid bilayer and proteins, constituting a checkpoint for the entry and passage of signals and other molecules. Their composition can be modulated by diet, pathophysiological processes, and nutritional/pharmaceutical interventions. In addition to their use as an energy source, lipids have important structural and functional roles, e.

The Novel Antitumor Compound HCA Promotes Glioma Cell Death by Inducing Endoplasmic Reticulum Stress and Autophagy.

Glioblastoma (GBM) is the most common and aggressive type of primary brain tumor in adults, and the median survival of patients with GBM is 14.5 months. Melitherapy is an innovative therapeutic approach to treat different diseases, including cancer, and it is based on the regulation of cell membrane composition and structure, which modulates relevant signal pathways.

2-Hydroxy-Docosahexaenoic Acid Is Converted Into Heneicosapentaenoic Acid via α-Oxidation: Implications for Alzheimer's Disease Therapy.

Alzheimer's disease (AD) is a neurodegenerative disease with as yet no efficient therapies, the pathophysiology of which is still largely unclear. Many drugs and therapies have been designed and developed in the past decade to stop or slow down this neurodegenerative process, although none has successfully terminated a phase-III clinical trial in humans. Most therapies have been inspired by the amyloid cascade hypothesis, which has more recently come under question due to the almost complete failure of clinical trials of anti-amyloid/tau therapies to date.

The Implications for Cells of the Lipid Switches Driven by Protein-Membrane Interactions and the Development of Membrane Lipid Therapy.

The cell membrane contains a variety of receptors that interact with signaling molecules. However, agonist-receptor interactions not always activate a signaling cascade. Amphitropic membrane proteins are required for signal propagation upon ligand-induced receptor activation.

The Opposing Contribution of SMS1 and SMS2 to Glioma Progression and Their Value in the Therapeutic Response to 2OHOA.

: 2-Hydroxyoleic acid (2OHOA) is particularly active against glioblastoma multiforme (GBM) and successfully finished a phase I/IIA trial in patients with glioma and other advanced solid tumors. However, its mechanism of action is not fully known. : The relationship between SMS1 and SMS2 expressions (mRNA) and overall survival in 329 glioma patients was investigated, and so was the correlation between SMS expression and 2OHOA's efficacy.

Minerval (2-hydroxyoleic acid) causes cancer cell selective toxicity by uncoupling oxidative phosphorylation and compromising bioenergetic compensation capacity.

This work tests bioenergetic and cell-biological implications of the synthetic fatty acid Minerval (2-hydroxyoleic acid), previously demonstrated to act by activation of sphingomyelin synthase in the plasma membrane (PM) and lowering of phosphatidylethanolamine (PE) and phosphatidylcholine (PC) and their carcinogenic signaling. We show here that Minerval also acts, selectively in cancer cell lines, as an ATP depleting uncoupler of mitochondrial oxidative phosphorylation (OxPhos). As a function of its exposure time, Minerval compromised the capacity of glioblastoma U87-MG cells to compensate for aberrant respiration by up-modulation of glycolysis.

The Secretion of miR-200s by a PKCζ/ADAR2 Signaling Axis Promotes Liver Metastasis in Colorectal Cancer.

Most colorectal cancer (CRC)-related deaths are due to liver metastases. PKCζ is a tumor suppressor in CRC with reduced expression in metastasis. Given the importance of microRNAs (miRNAs) in regulating cellular plasticity, we performed an unbiased screening and identified the miR-200 family as the most relevant miRNAs downregulated by PKCζ deficiency.

G protein-membrane interactions II: Effect of G protein-linked lipids on membrane structure and G protein-membrane interactions.

G proteins often bear myristoyl, palmitoyl and isoprenyl moieties, which favor their association with the membrane and their accumulation in G Protein Coupled Receptor-rich microdomains. These lipids influence the biophysical properties of membranes and thereby modulate G protein binding to bilayers. In this context, we showed here that geranylgeraniol, but neither myristate nor palmitate, increased the inverted hexagonal (H) phase propensity of phosphatidylethanolamine-containing membranes.

Control of Paneth Cell Fate, Intestinal Inflammation, and Tumorigenesis by PKCλ/ι.

Paneth cells are a highly specialized population of intestinal epithelial cells located in the crypt adjacent to Lgr5(+) stem cells, from which they differentiate through a process that requires downregulation of the Notch pathway. Their ability to store and release antimicrobial peptides protects the host from intestinal pathogens and controls intestinal inflammation. Here, we show that PKCλ/ι is required for Paneth cell differentiation at the level of Atoh1 and Gfi1, through the control of EZH2 stability by direct phosphorylation.

G protein-membrane interactions I: Gαi1 myristoyl and palmitoyl modifications in protein-lipid interactions and its implications in membrane microdomain localization.

G proteins are fundamental elements in signal transduction involved in key cell responses, and their interactions with cell membrane lipids are critical events whose nature is not fully understood. Here, we have studied how the presence of myristic and palmitic acid moieties affects the interaction of the Gαi1 protein with model and biological membranes. For this purpose, we quantified the binding of purified Gαi1 protein and Gαi1 protein acylation mutants to model membranes, with lipid compositions that resemble different membrane microdomains.

Repression of Intestinal Stem Cell Function and Tumorigenesis through Direct Phosphorylation of β-Catenin and Yap by PKCζ.

Intestinal epithelial homeostasis requires continuous renewal supported by stem cells located in the base of the crypt. Disruption of this balance results in failure to regenerate and initiates tumorigenesis. The β-catenin and Yap pathways in Lgr5 stem cells have been shown to be central to this process.

Regulation of the cancer cell membrane lipid composition by NaCHOleate: effects on cell signaling and therapeutical relevance in glioma.

This review summarizes the cellular bases of the effects of NaCHOleate (2-hydroxyoleic acid; 2OHOA; Minerval) against glioma and other types of tumors. NaCHOleate, activates sphingomyelin synthase (SGMS) increasing the levels of cell membrane sphingomyelin (SM) and diacylglycerol (DAG) together with reductions of phosphatidylethanolamine (PE) and phosphatidylcholine (PC). The increases in the membrane levels of NaCHOleate itself and of DAG induce a translocation and overexpression of protein kinase C (PKC) and subsequent reductions of Cyclin D, cyclin-dependent kinases 4 and 6 (CDKs 4 and 6), hypophosphorylation of the retinoblastoma protein, inhibition of E2F1 and knockdown of dihydrofolate reductase (DHFR) impairing DNA synthesis.

Oral caffeine administration ameliorates acute colitis by suppressing chitinase 3-like 1 expression in intestinal epithelial cells.

Background: The initial trigger of inflammatory bowel disease (IBD) can be partly attributed towards the interaction and invasion of intestinal epithelial cells (IECs) and submucosal compartments. Identifying safe and economical methods to block these interactions may help prevent the onset of early colitis. Chitinase 3-like 1 (CHI3L1) is an inducible host protein that facilitates bacterial attachment and invasion on/into IECs.

Control of nutrient stress-induced metabolic reprogramming by PKCζ in tumorigenesis.

Tumor cells have high-energetic and anabolic needs and are known to adapt their metabolism to be able to survive and keep proliferating under conditions of nutrient stress. We show that PKCζ deficiency promotes the plasticity necessary for cancer cells to reprogram their metabolism to utilize glutamine through the serine biosynthetic pathway in the absence of glucose. PKCζ represses the expression of two key enzymes of the pathway, PHGDH and PSAT1, and phosphorylates PHGDH at key residues to inhibit its enzymatic activity.

Normalization of sphingomyelin levels by 2-hydroxyoleic acid induces autophagic cell death of SF767 cancer cells.

The very high mortality rate of gliomas reflects the unmet therapeutic need associated with this type of brain tumor. We have discovered that the plasma membrane fulfills a critical role in the propagation of tumorigenic signals, whereby changes in membrane lipid content can either activate or silence relevant pathways. We have designed a synthetic fatty acid, 2-hydroxyoleic acid (2OHOA), that specifically activates sphingomyelin synthase (SGMS), thereby modifying the lipid content of cancer cell membranes and restoring lipid levels to those found in normal cells.

2-Hydroxyoleate, a nontoxic membrane binding anticancer drug, induces glioma cell differentiation and autophagy.

Despite recent advances in the development of new cancer therapies, the treatment options for glioma remain limited, and the survival rate of patients has changed little over the past three decades. Here, we show that 2-hydroxyoleic acid (2OHOA) induces differentiation and autophagy of human glioma cells. Compared to the current reference drug for this condition, temozolomide (TMZ), 2OHOA combated glioma more efficiently and, unlike TMZ, tumor relapse was not observed following 2OHOA treatment.

Chitin microparticles for the control of intestinal inflammation.

Background: Chitin is a polymer of N-acetylglucosamine with the ability to regulate innate and adaptive immune responses. However, the detailed mechanisms of chitin-mediated regulation of intestinal inflammation are only partially known.

Methods: In this study chitin microparticles (CMPs) or phosphate-buffered saline (PBS) were orally administered to acute and chronic colitis models every 3 days for 6 consecutive weeks beginning at weaning age.

Chitinase 3-like-1 expression in colonic epithelial cells as a potentially novel marker for colitis-associated neoplasia.

Chitinase 3-like-1 (CHI3L1/YKL-40) is a protein secreted from restricted cell types including colonic epithelial cells (CECs) and macrophages. CHI3L1 is an inflammation-associated molecule, and its expression is enhanced in persons with colitis and colon cancer. The biological function of CHI3L1 on CECs is unclear.