scholarly journals GM2-GM3 gangliosides ratio is dependent on GRP94 through down-regulation of GM2-AP cofactor in brain metastasis cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Carmen Bedia ◽  
Miriam Badia ◽  
Laia Muixí ◽  
Thierry Levade ◽  
Romà Tauler ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Critical Role ◽  
Surface Dynamics ◽  
Oncogenic Signaling ◽  
Cell Behaviour ◽  
Lipid Species ◽  
Lysosomal Accumulation ◽  
Oncogenic Signaling Pathways ◽  
Hydrolysis Of

Abstract GRP94 is an ATP-dependent chaperone able to regulate pro-oncogenic signaling pathways. Previous studies have shown a critical role of GRP94 in brain metastasis (BrM) pathogenesis and progression. In this work, an untargeted lipidomic analysis revealed that some lipid species were altered in GRP94-deficient cells, specially GM2 and GM3 gangliosides. The catalytic pathway of GM2 is affected by the low enzymatic activity of β-Hexosaminidase (HexA), responsible for the hydrolysis of GM2 to GM3. Moreover, a deficiency of the GM2-activator protein (GM2-AP), the cofactor of HexA, is observed without alteration of gene expression, indicating a post-transcriptional alteration of GM2-AP in the GRP94-ablated cells. One plausible explanation of these observations is that GM2-AP is a client of GRP94, resulting in defective GM2 catabolic processing and lysosomal accumulation of GM2 in GRP94-ablated cells. Overall, given the role of gangliosides in cell surface dynamics and signaling, their imbalance might be linked to modifications of cell behaviour acquired in BrM progression. This work indicates that GM2-AP could be an important factor in ganglioside balance maintenance. These findings highlight the relevance of GM3 and GM2 gangliosides in BrM and reveal GM2-AP as a promising diagnosis and therapeutic target in BrM research.

scholarly journals WNT Signaling: an Emerging Mediator of Cancer Cell Metabolism?

2014 ◽  
Vol 35 (1) ◽  
pp. 2-10 ◽  
Author(s):  
Victoria Sherwood
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathways ◽  
Cancer Cell ◽  
Cancer Metabolism ◽  
Cell Metabolism ◽  
Critical Role ◽  
Oncogenic Signaling ◽  
Cancer Cell Metabolism ◽  
Oncogenic Signaling Pathways

WNT signaling was discovered in tumor models and has been recognized as a regulator of cancer development and progression for over 3 decades. Recent work has highlighted a critical role for WNT signaling in the metabolic homeostasis of mammals, where its misregulation has been heavily implicated in diabetes. While the majority of WNT metabolism research has focused on nontransformed tissues, the role of WNT in cancer metabolism remains underinvestigated. Cancer is also a metabolic disease where oncogenic signaling pathways regulate energy production and macromolecular synthesis to fuel rapidly proliferating tumors. This review highlights the emerging evidence for WNT signaling in the reprogramming of cancer cell metabolism and examines the role of these signaling pathways as mediators of tumor bioenergetics.

scholarly journals The Critical Role of Reductive Steps in the Nickel‐Catalyzed Hydrogenolysis and Hydrolysis of Aryl Ether C−O Bonds

2019 ◽  
Vol 59 (4) ◽  
pp. 1445-1449 ◽  
Author(s):  
Meng Wang ◽  
Yuntao Zhao ◽  
Donghai Mei ◽  
R. Morris Bullock ◽  
Oliver Y. Gutiérrez ◽  
...  
Keyword(s):  
Critical Role ◽  
Aryl Ether ◽  
Hydrolysis Of

scholarly journals IL1RAP potentiates multiple oncogenic signaling pathways in AML

2018 ◽  
Vol 215 (6) ◽  
pp. 1709-1727 ◽  
Author(s):  
Kelly Mitchell ◽  
Laura Barreyro ◽  
Tihomira I. Todorova ◽  
Samuel J. Taylor ◽  
Iléana Antony-Debré ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Interleukin 1 ◽  
Oncogenic Signaling ◽  
Genetic Deletion ◽  
Mechanistic Basis ◽  
Oncogenic Signaling Pathways ◽  
Receptor Accessory Protein

The surface molecule interleukin-1 receptor accessory protein (IL1RAP) is consistently overexpressed across multiple genetic subtypes of acute myeloid leukemia (AML) and other myeloid malignancies, including at the stem cell level, and is emerging as a novel therapeutic target. However, the cell-intrinsic functions of IL1RAP in AML cells are largely unknown. Here, we show that targeting of IL1RAP via RNA interference, genetic deletion, or antibodies inhibits AML pathogenesis in vitro and in vivo, without perturbing healthy hematopoietic function or viability. Furthermore, we found that the role of IL1RAP is not restricted to the IL-1 receptor pathway, but that IL1RAP physically interacts with and mediates signaling and pro-proliferative effects through FLT3 and c-KIT, two receptor tyrosine kinases with known key roles in AML pathogenesis. Our study provides a new mechanistic basis for the efficacy of IL1RAP targeting in AML and reveals a novel role for this protein in the pathogenesis of the disease.

scholarly journals Molecular biology of bcr-abl1–positive chronic myeloid leukemia

Blood ◽  
2009 ◽  
Vol 113 (8) ◽  
pp. 1619-1630 ◽  
Author(s):  
Alfonso Quintás-Cardama ◽  
Jorge Cortes
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Current Knowledge ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Oncogenic Signaling ◽  
Stem Cell Quiescence ◽  
Oncogenic Signaling Pathways

Abstract Chronic myeloid leukemia (CML) has been regarded as the paradigmatic example of a malignancy defined by a unique molecular event, the BCR-ABL1 oncogene. Decades of research zeroing in on the role of BCR-ABL1 kinase in the pathogenesis of CML have culminated in the development of highly efficacious therapeutics that, like imatinib mesylate, target the oncogenic kinase activity of BCR-ABL1. In recent years, most research efforts in CML have been devoted to developing novel tyrosine kinase inhibitors (TKIs) as well as to elucidating the mechanisms of resistance to imatinib and other TKIs. Nonetheless, primordial aspects of the pathogenesis of CML, such as the mechanisms responsible for the transition from chronic phase to blast crisis, the causes of genomic instability and faulty DNA repair, the phenomenon of stem cell quiescence, the role of tumor suppressors in TKI resistance and CML progression, or the cross-talk between BCR-ABL1 and other oncogenic signaling pathways, still remain poorly understood. Herein, we synthesize the most relevant and current knowledge on such areas of the pathogenesis of CML.

scholarly journals A Blood Pact: the Significance and Implications of eIF4E on Lymphocytic Leukemia

2018 ◽  
pp. 363-382
Author(s):  
V. VENTURI ◽  
T. MASEK ◽  
M. POSPISEK
Keyword(s):  
Translational Control ◽  
Lymphoblastic Leukemia ◽  
Lymphocytic Leukemia ◽  
Initiation Factor ◽  
Oncogenic Signaling ◽  
Translation Factor ◽  
Eukaryotic Initiation Factor 4E ◽  
Biological Circuits ◽  
Oncogenic Signaling Pathways

Elevated levels of eukaryotic initiation factor 4E (eIF4E) are implicated in neoplasia, with cumulative evidence pointing to its role in the etiopathogenesis of hematological diseases. As a node of convergence for several oncogenic signaling pathways, eIF4E has attracted a great deal of interest from biologists and clinicians whose efforts have been targeting this translation factor and its biological circuits in the battle against leukemia. The role of eIF4E in myeloid leukemia has been ascertained and drugs targeting its functions have found their place in clinical trials. Little is known, however, about the pertinence of eIF4E to the biology of lymphocytic leukemia and a paucity of literature is available in this regard that prospectively evaluates the topic to guide practice in hematological cancer. A comprehensive analysis on the significance of eIF4E translation factor in the clinical picture of leukemia arises, therefore, as a compelling need. This review presents aspects of eIF4E involvement in the realm of the lymphoblastic leukemia status; translational control of immunological function via eIF4E and the state-of-the-art in drugs will also be outlined.

scholarly journals Critical Role of Virion-Associated Cholesterol and Sphingolipid in Hepatitis C Virus Infection

2008 ◽  
Vol 82 (12) ◽  
pp. 5715-5724 ◽  
Author(s):  
Hideki Aizaki ◽  
Kenichi Morikawa ◽  
Masayoshi Fukasawa ◽  
Hiromichi Hara ◽  
Yasushi Inoue ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Cell Attachment ◽  
Critical Role ◽  
Molar Ratio ◽  
Complete Life Cycle ◽  
Rna Accumulation ◽  
Hydrolysis Of ◽  
Hcv Structural Proteins

ABSTRACT In this study, we establish that cholesterol and sphingolipid associated with hepatitis C virus (HCV) particles are important for virion maturation and infectivity. In a recently developed culture system enabling study of the complete life cycle of HCV, mature virions were enriched with cholesterol as assessed by the molar ratio of cholesterol to phospholipid in virion and cell membranes. Depletion of cholesterol from the virus or hydrolysis of virion-associated sphingomyelin almost completely abolished HCV infectivity. Supplementation of cholesterol-depleted virus with exogenous cholesterol enhanced infectivity to a level equivalent to that of the untreated control. Cholesterol-depleted or sphingomyelin-hydrolyzed virus had markedly defective internalization, but no influence on cell attachment was observed. Significant portions of HCV structural proteins partitioned into cellular detergent-resistant, lipid-raft-like membranes. Combined with the observation that inhibitors of the sphingolipid biosynthetic pathway block virion production, but not RNA accumulation, in a JFH-1 isolate, our findings suggest that alteration of the lipid composition of HCV particles might be a useful approach in the design of anti-HCV therapy.

scholarly journals THE YKI-CACTUS (IKBα)-JNK AXIS PROMOTES TUMOR GROWTH AND PROGRESSION IN DROSOPHILA

2020 ◽  
Author(s):  
Kirti Snigdha ◽  
Amit Singh ◽  
Madhuri Kango-Singh
Keyword(s):  
Tumor Progression ◽  
Tumor Cells ◽  
Critical Role ◽  
Suppressor Gene ◽  
Inflammatory Factors ◽  
Oncogenic Signaling ◽  
Jnk Pathway ◽  
Target Matrix ◽  
Necrosis Factor

AbstractPresence of inflammatory factors in the tumor microenvironment is well known yet their specific role in tumorigenesis is elusive. The core inflammatory pathways are conserved in Drosophila, including the Toll-Like Receptor (TLR) and the Tumor Necrosis Factor (TNF) pathway. We used Drosophila tumor models to study the role of inflammatory factors in tumorigenesis. Specifically, we co-activated oncogenic forms of RasV12 or its major effector Yorkie (Yki3SA) in polarity deficient cells mutant for tumor suppressor gene scribble (scrib) marked by GFP under nubGAL4 or in somatic clones. This system recapitulates the clonal origins of cancer, and shows neoplastic growth, invasion and lethality. We investigated if TLR and TNF pathway affect growth of Yki3SAscribRNAi or RasV12scribRNAi tumors through activation of tumor promoting Jun N-terminal Kinase (JNK) pathway and its target Matrix Metalloprotease1 (MMP1). We report, TLR component, Cactus (Cact) is highly upregulated in Yki3SAscribRNAi or RasV12scribRNAi tumors. Drosophila Cactus (mammalian IKBα) acts as an inhibitor of NFKB signaling that plays key roles in inflammatory and immune response. Here we show an alternative role for Cactus, and by extension cytokine mediated signaling, in tumorigenesis. Downregulating Cact affects both tumor progression and invasion. Interestingly, downregulating TNF receptors in tumor cells did not affect their invasiveness despite reducing JNK activity. Genetic analysis suggested that Cact and JNK are key regulators of tumor progression. Overall, we show that Yki plays a critical role in tumorigenesis by controlling Cact, which in turn, mediates tumor promoting JNK oncogenic signaling in tumor cells.

scholarly journals Targeting PAK1

2017 ◽  
Vol 45 (1) ◽  
pp. 79-88 ◽  
Author(s):  
Galina Semenova ◽  
Jonathan Chernoff
Keyword(s):  
Signaling Pathways ◽  
Peptide Inhibitors ◽  
Oncogenic Signaling ◽  
Allosteric Inhibitors ◽  
Small Molecule Inhibition ◽  
Pharmacokinetic Properties ◽  
Competitive Inhibitors ◽  
P21 Activated Kinase ◽  
Oncogenic Signaling Pathways

p21-Activated kinase 1 (PAK1) has attracted much attention as a potential therapeutic target due to its central role in many oncogenic signaling pathways, its frequent dysregulation in cancers and neurological disorders, and its tractability as a target for small-molecule inhibition. To date, several PAK1-targeting compounds have been developed as preclinical agents, including one that has been evaluated in a clinical trial. A series of ATP-competitive inhibitors, allosteric inhibitors and peptide inhibitors with distinct biochemical and pharmacokinetic properties represent useful laboratory tools for studies on the role of PAK1 in biology and in disease contexts, and could lead to promising therapeutic agents. Given the central role of PAK1 in vital signaling pathways, future clinical development of PAK1 inhibitors will require careful investigation of their safety and efficacy.

scholarly journals Regulation of Canonical Oncogenic Signaling Pathways in Cancer via DNA Methylation

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3199
Author(s):  
Jennifer Lu ◽  
Premila Wilfred ◽  
Darren Korbie ◽  
Matt Trau
Keyword(s):  
Dna Methylation ◽  
Signaling Pathways ◽  
Biomarker Discovery ◽  
Oncogenic Signaling ◽  
Tissue Samples ◽  
Epigenetic Biomarkers ◽  
Differentially Methylated Genes ◽  
Oncogenic Signaling Pathways ◽  
Integration Analysis

Disruption of signaling pathways that plays a role in the normal development and cellular homeostasis may lead to the dysregulation of cellular signaling and bring about the onset of different diseases, including cancer. In addition to genetic aberrations, DNA methylation also acts as an epigenetic modifier to drive the onset and progression of cancer by mediating the reversible transcription of related genes. Although the role of DNA methylation as an alternative driver of carcinogenesis has been well-established, the global effects of DNA methylation on oncogenic signaling pathways and the presentation of cancer is only emerging. In this article, we introduced a differential methylation parsing pipeline (MethylMine) which mined for epigenetic biomarkers based on feature selection. This pipeline was used to mine for biomarkers, which presented a substantial difference in methylation between the tumor and the matching normal tissue samples. Combined with the Data Integration Analysis for Biomarker discovery (DIABLO) framework for machine learning and multi-omic analysis, we revisited the TCGA DNA methylation and RNA-Seq datasets for breast, colorectal, lung, and prostate cancer, and identified differentially methylated genes within the NRF2-KEAP1/PI3K oncogenic pathway, which regulates the expression of cytoprotective genes, that serve as potential therapeutic targets to treat different cancers.

Sign in / Sign up

Export Citation Format

Share Document