Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
Add more filters










Database
Language
Publication year range
1.
PLoS One ; 17(12): e0278711, 2022.
Article in English | MEDLINE | ID: mdl-36477459

ABSTRACT

Breast cancer is heterogenous in development and cell population with prognoses being highly dependent on numerous factors from driving mutations, biomarker expression and variation in extracellular environment, all affecting response to therapies. Recently, much attention has been given to the role of metabolic alteration in cancers, expanding from the Warburg effect to highlight unique patterns in different cancer cell populations for improving diagnostic and therapeutic approaches. We recently reported on modulation of mannosylation of α-dystroglycan with the metabolite ribitol in breast cancer lines. Here we investigate the effects of pentose sugars ribitol, ribose, and xylitol media supplementation in breast cancer cells by metabolomics and differential gene expression profiling. This combined approach revealed distinctive patterns of alterations in metabolic pathways by ribitol, contrasted with the closely related pentose ribose and pentitol xylitol. Significantly, ribitol supplementation enhances utilization of glucose by glycolysis, whereas ribose improves oxidative phosphorylation and fatty acid synthesis. Ribitol supplementation also increased levels of reduced glutathione (associated with a decrease in oxidative phosphorylation, gluconeogenesis), where ribose supplementation elevated levels of oxidized glutathione (GSSG) indicating an increase in oxidative stress. Treatment with ribitol also enhanced nucleotide biosynthesis. The apparent TCA cycle dysregulation, with distinctive pattern in response to the individual pentitol and pentose, such as ribitol increasing succinate and fumarate while decreasing citrate, demonstrate the adaptive capability of cancer cells to nutritional environment. This metabolic reprogramming presents new avenues for developing targeted therapies to cancers with metabolites, especially in combination with other drug treatments.


Subject(s)
Neoplasms , Ribitol , Carbon , Ribose , Metabolic Networks and Pathways , Gene Expression Profiling
2.
PLoS One ; 17(12): e0278482, 2022.
Article in English | MEDLINE | ID: mdl-36454905

ABSTRACT

Limb Girdle Muscular Dystrophy 2I (LGMDR9) is one of the most common LGMD characterized by defects in glycosylation of α-dystroglycan (matriglycan) resulting from mutations of Fukutin-related protein (FKRP). There is no effective therapy currently available. We recently demonstrated that ribitol supplement increases levels of matriglycan in cells in vitro and in FKRP-P448L (P448L) mutant mouse model through drinking water administration. To be clinically relevant, we have now conducted a dose-escalating efficacy study by gavage in P448L mutant mice. Six months of ribitol treatment daily significantly rescued functions of skeletal, respiratory, and cardiac muscles dose-dependently. This was associated with a dose dependent increase in matriglycan and improvement in muscle pathology with reductions in muscle degeneration, inflammatory infiltration and fibrosis. Importantly, ribitol significantly increased life span and muscle functions of the female animals receiving treatment from 10 months of age. The only observed side effect was gastrointestinal tract bloating with loose stool and this effect is also dose dependent. The results validate the mechanism that ribitol as a pre-substrate of glycosyltransferase is able to compensate for the decreased function of mutant FKRP with restoration of matriglycan expression and provide a guidance for future clinical trial design.


Subject(s)
Muscular Dystrophies, Limb-Girdle , Musculoskeletal Physiological Phenomena , Female , Mice , Animals , Ribitol , Longevity , Disease Models, Animal , Muscles , Pentosyltransferases/genetics
3.
Mol Ther ; 21(10): 1832-40, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23817215

ABSTRACT

Mutations in the FKRP gene are associated with a wide range of muscular dystrophies from mild limb-girdle muscular dystrophy (LGMD) 2I to severe Walker-Warburg syndrome and muscle-eye-brain disease. The characteristic biochemical feature of these diseases is the hypoglycosylation of α-dystroglycan (α-DG). Currently there is no effective treatment available. In this study, we examined the adeno-associated virus serotype 9 vector (AAV9)-mediated gene therapy in the FKRP mutant mouse model with a proline to leucine missense mutation (P448L). Our results showed that intraperitoneal administration of AAV9-FKRP resulted in systemic FKRP expression in all striated muscles examined with the highest levels in cardiac muscle. Consistent with our previous observations, FKRP protein is localized in the Golgi apparatus in myofibers. Expression of FKRP consequently restored functional glycosylation of α-DG in the skeletal and cardiac muscles. Significant improvement in dystrophic pathology, serum creatine kinase levels and muscle function was observed. Only limited FKRP transgene expression was detected in kidney and liver with no detectable toxicity. Our results provided evidence for the utility of AAV-mediated gene replacement therapy for FKRP-related muscular dystrophies.


Subject(s)
Dependovirus/genetics , Dystroglycans/metabolism , Genetic Therapy/methods , Muscle, Skeletal/physiology , Muscular Dystrophies, Limb-Girdle/therapy , Muscular Dystrophy, Animal/therapy , Proteins/genetics , Animals , Cells, Cultured , Disease Models, Animal , Genetic Vectors , Glycosylation , Injections, Intraperitoneal , Mice , Mice, Inbred C57BL , Mice, Transgenic , Muscular Dystrophies, Limb-Girdle/metabolism , Muscular Dystrophies, Limb-Girdle/physiopathology , Pentosyltransferases , Proteins/metabolism , Transferases , Transgenes
4.
Int J Cancer ; 101(6): 581-8, 2002 Oct 20.
Article in English | MEDLINE | ID: mdl-12237901

ABSTRACT

The PLU-1 gene is expressed at the level of message in breast cancers and breast cancer cell lines and shows restricted expression in normal adult tissues with the exception of testis. The predicted protein sequence contains several domains, including the PLU domain, which is shared by other proteins involved in transcription and/or development. We have developed a polyclonal antiserum to a C-terminal fragment of the PLU-1 protein, which shows little homology to other family members. Immunohistochemical analysis with the antiserum alpha-PLU-1C confirmed the nuclear localisation of PLU-1. alpha-PLU-1C also reacted with the mouse homologue of PLU-1 (mPlu-1) but not with the closest family member, RBP2. Using Western blot analysis, PLU-1 was shown to be well expressed in breast cancers and breast cancer cell lines, while it was not detected in a range of normal adult tissues. Our results suggest that the PLU-1 protein may belong to the class of testis/cancer antigens.


Subject(s)
Antigens, Neoplasm/metabolism , Breast Neoplasms/metabolism , DNA-Binding Proteins/metabolism , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Neoplasm Proteins/metabolism , Testis/metabolism , Amino Acid Sequence , Animals , Antigens, Neoplasm/chemistry , Antigens, Neoplasm/genetics , Blotting, Western , COS Cells , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/genetics , Humans , Jumonji Domain-Containing Histone Demethylases , Male , Mice , Molecular Sequence Data , Neoplasm Proteins/chemistry , Neoplasm Proteins/genetics , Nuclear Proteins , Organ Specificity , RNA, Messenger/genetics , RNA, Messenger/metabolism , Repressor Proteins , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, Cultured , Up-Regulation
5.
Gene Expr Patterns ; 2(3-4): 275-82, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12617814

ABSTRACT

PLU-1 is a novel breast cancer associated nuclear protein containing highly conserved domains including the PLU domain, putative DNA/chromatin binding motifs, and PHD/LAP domains. Here we report the cloning of the mouse homologue (Plu-1), and document its expression in adult tissues, mammary tumours and the embryo. The overall homology with human PLU-1 is 94% at the protein level, with almost 100% identity in the conserved domains, suggesting functional conservation. As with human PLU-1 the expression of Plu-1 in adult tissues is restricted, with high expression being seen only in testis, while expression in mammary tumours from c-neu transgenic mice is high. Plu-1 is also differentially expressed in the adult mammary gland. In the developing embryo Plu-1 is expressed in a temporally restricted fashion with tissue specific expression being limited to parts of the developing brain, whisker follicle, mammary bud, thymus, limbs, intervertebral disc, olfactory epithelium, teeth, eye, and stomach. The temporal and spatial expression patterns of the transcription factors Bf-1 and Pax9, recently found to bind to PLU-1 through the PLU domain overlap with Plu-1 expression during development. Thus Plu-1 appears to play an important role in mouse embryonic development which may involve interaction with Pax9 and Bf-1.


Subject(s)
DNA-Binding Proteins/genetics , Mammary Glands, Animal/metabolism , Mammary Neoplasms, Animal/metabolism , Neoplasm Proteins/genetics , Animals , Cell Differentiation/physiology , DNA-Binding Proteins/metabolism , Forkhead Transcription Factors , Gene Expression Regulation, Developmental , Gene Expression Regulation, Neoplastic , Humans , Immunoblotting , Jumonji Domain-Containing Histone Demethylases , Mammary Glands, Animal/embryology , Mice/embryology , Mice, Knockout , Molecular Sequence Data , Neoplasm Proteins/metabolism , Nerve Tissue Proteins/metabolism , Nuclear Proteins , PAX9 Transcription Factor , Repressor Proteins , Telencephalon/embryology , Telencephalon/metabolism , Tooth/embryology , Transcription Factors/genetics , Transcription Factors/metabolism
6.
Mech Dev ; 119 Suppl 1: S239-46, 2002 Dec.
Article in English | MEDLINE | ID: mdl-14516692

ABSTRACT

PLU-1 is a novel breast cancer associated nuclear protein containing highly conserved domains including the PLU domain, putative DNA/chromatin binding motifs, and PHD/LAP domains. Here we report the cloning of the mouse homologue (Plu-1), and document its expression in adult tissues, mammary tumours and the embryo. The overall homology with human PLU-1 is 94% at the protein level, with almost 100% identity in the conserved domains, suggesting functional conservation. As with human PLU-1 the expression of Plu-1 in adult tissues is restricted, with high expression being seen only in testis, while expression in mammary tumours from c-neu transgenic mice is high. Plu-1 is also differentially expressed in the adult mammary gland. In the developing embryo Plu-1 is expressed in a temporally restricted fashion with tissue specific expression being limited to parts of the developing brain, whisker follicle, mammary bud, thymus, limbs, intervertebral disc, olfactory epithelium, teeth, eye, and stomach. The temporal and spatial expression patterns of the transcription factors Bf-1 and Pax9, recently found to bind to PLU-1 through the PLU domain overlap with Plu-1 expression during development. Thus Plu-1 appears to play an important role in mouse embryonic development which may involve interaction with Pax9 and Bf-1.


Subject(s)
Jumonji Domain-Containing Histone Demethylases , Nuclear Proteins , Amino Acid Sequence , Animals , Breast Neoplasms , Gene Expression Regulation, Developmental , Humans , Mice , Molecular Sequence Data , Nuclear Proteins/metabolism , Repressor Proteins/genetics , Transcription Factors/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...