Peroxiredoxin-1 Tyr194 phosphorylation regulates LOX-dependent extracellular matrix remodelling in breast cancer.

BACKGROUND: Peroxiredoxin 1 (PRDX1) belongs to an abundant family of peroxidases whose role in cancer is still unresolved. While mouse knockout studies demonstrate a tumour suppressive role for PRDX1, in cancer cell xenografts, results denote PRDX1 as a drug target. Probably, this phenotypic discrepancy stems from distinct roles of PRDX1 in certain cell types or stages of tumour progression. METHODS: We demonstrate an important cell-autonomous function for PRDX1 utilising a syngeneic mouse model (BALB/c) and mammary fibroblasts (MFs) obtained from it. RESULTS: Loss of PRDX1 in vivo promotes collagen remodelling known to promote breast cancer progression. PRDX1 inactivation in MFs occurs via SRC-induced phosphorylation of PRDX1 TYR194 and not through the expected direct oxidation of CYS52 in PRDX1 by ROS. TYR194-phosphorylated PRDX1 fails to bind to lysyl oxidases (LOX) and leads to the accumulation of extracellular LOX proteins which supports enhanced collagen remodelling associated with breast cancer progression. CONCLUSIONS: This study reveals a cell type-specific tumour suppressive role for PRDX1 that is supported by survival analyses, depending on PRDX1 protein levels in breast cancer cohorts.

The peroxidase PRDX1 inhibits the activated phenotype in mammary fibroblasts through regulating c-Jun N-terminal kinases.

BACKGROUND: Reactive oxygen species (ROS), including hydrogen peroxide, drive differentiation of normal fibroblasts into activated fibroblasts, which can generate high amounts of hydrogen peroxide themselves, thereby increasing oxidative stress in the microenvironment. This way, activated fibroblasts can transition into cancer-associated fibroblasts (CAFs). METHODS: Mammary fibroblasts from either female 8 weeks old PRDX1 knockout and wildtype mice or Balb/c mice were studied for characteristic protein expression using immunofluorescence and immunoblotting. Cancer-associated fibroblasts was examined by transwell migration and invasion assays. The binding of PRDX1 to JNK1 was assessed by co-immuneprecipitation and JNK regulation of CAF phenotypes was examined using the JNK inhibitor SP600125. Extracellular hydrogen peroxide levels were measured by chemiluminescence via the reaction between hypochlorite and luminol. Statistical analyses were done using Students t-test. RESULTS: We show here PRDX1 activity as an essential switch in regulating the activated phenotype as loss of PRDX1 results in the development of a CAF-like phenotype in mammary fibroblasts. We also show that PRDX1 regulates JNK kinase signaling thereby inhibiting CAF-like markers and CAF invasion. Inhibition of JNK activity reduced these behaviors. CONCLUSIONS: These data suggest that PRDX1 repressed the activated phenotype of fibroblasts in part through JNK inhibition which may present a novel therapeutic option for CAF-enriched cancers such as breast cancer.

Redoxins as gatekeepers of the transcriptional oxidative stress response.

Transcription factors control the rate of transcription of genetic information from DNA to messenger RNA, by binding specific DNA sequences in promoter regions. Transcriptional gene control is a rate-limiting process that is tightly regulated and based on transient environmental signals which are translated into long-term changes in gene transcription. Post-translational modifications (PTMs) on transcription factors by phosphorylation or acetylation have profound effects not only on sub-cellular localization but also on substrate specificity through changes in DNA binding capacity. During times of cellular stress, specific transcription factors are in place to help protect the cell from damage by initiating the transcription of antioxidant response genes. Here we discuss PTMs caused by reactive oxygen species (ROS), such as H2O2, that can expeditiously regulate the activation of transcription factors involved in the oxidative stress response. Part of this rapid regulation are proteins involved in H2O2-related reduction and oxidation (redox) reactions such as redoxins, H2O2 scavengers described to interact with transcription factors. Redoxins have highly reactive cysteines of rate constants around 6-10-1 s-1 that engage in nucleophilic substitution of a thiol-disulfide with another thiol in inter-disulfide exchange reactions. We propose here that H2O2 signal transduction induced inter-disulfide exchange reactions between redoxin cysteines and cysteine thiols of transcription factors to allow for rapid and precise on and off switching of transcription factor activity. Thus, redoxins are essential modulators of stress response pathways beyond H2O2 scavenging capacity.

A Peroxidase Peroxiredoxin 1-Specific Redox Regulation of the Novel FOXO3 microRNA Target let-7.

Precision in redox signaling is attained through posttranslational protein modifications such as oxidation of protein thiols. The peroxidase peroxiredoxin 1 (PRDX1) regulates signal transduction through changes in thiol oxidation of its cysteines. We demonstrate here that PRDX1 is a binding partner for the tumor suppressive transcription factor FOXO3 that directly regulates the FOXO3 stress response. Heightened oxidative stress evokes formation of disulfide-bound heterotrimers linking dimeric PRDX1 to monomeric FOXO3. Absence of PRDX1 enhances FOXO3 nuclear localization and transcription that are dependent on the presence of Cys31 or Cys150 within FOXO3. Notably, FOXO3-T32 phosphorylation is constitutively enhanced in these mutants, but nuclear translocation of mutant FOXO3 is restored with PI3K inhibition. Here we show that on H2O2 exposure, transcription of tumor suppressive miRNAs let-7b and let-7c is regulated by FOXO3 or PRDX1 expression levels and that let-7c is a novel target for FOXO3. Conjointly, inhibition of let-7 microRNAs increases let-7-phenotypes in PRDX1-deficient breast cancer cells. Altogether, these data ascertain the existence of an H2O2-sensitive PRDX1-FOXO3 signaling axis that fine tunes FOXO3 activity toward the transcription of gene targets in response to oxidative stress. Antioxid. Redox Signal. 28, 62-77.

Quality of life and diabetes knowledge of young persons with type 1 diabetes: Influence of treatment modalities and demographics.

OBJECTIVE: The primary objective of this descriptive study was to assess the perception of quality of life and diabetes knowledge among young persons with type 1 diabetes. The secondary objectives were to examine the influence of treatment modality (continuous subcutaneous insulin infusion vs multiple daily injections) and demographics on quality of life and diabetes knowledge of these young persons and to determine the associations between the study variables. RESEARCH DESIGN AND METHODS: Participants aged 9 to 17 years (n=103) completed the diabetes-specific measure of quality of life and a diabetes knowledge test. Parents of these young persons completed a history questionnaire. Descriptive statistics, independent t tests, and Pearson's correlations were used to analyze the data. RESULTS: Overall, diabetes-specific measure of quality-of-life scores indicated good quality of life among the study population. Mean scores on the impact, worry, and satisfaction subscales did not indicate negative perceptions of the disease. Body mass index was significantly inversely correlated with the satisfaction scale ( r =-0.247, P =.023). Self-rated health was negatively correlated with the impact ( r =-0.221, P =.038) and worry scale ( r =-0.294, P =.004) and positively correlated with the satisfaction scale ( r =0.291, P =.004). Seventy-two percent correct responses were given on the diabetes knowledge test. Knowledge was significantly correlated to diabetes diagnosis age ( r =0.276, P =.009) and current age ( r =0.453, P =.0005). No significant differences were observed between participants using continuous subcutaneous insulin infusion vs multiple daily injections in regard to diabetes-specific measure of quality of life and diabetes knowledge test. CONCLUSIONS: In our study, young persons with type 1 diabetes had a positive perception of their quality of life and above-average diabetes knowledge, which were influenced by several factors, such as self-rated health, body mass index, and age at diagnosis. Dietetics professionals should assess perceived quality of life and knowledge among young persons with type 1 diabetes because these factors can potentially influence disease management and treatment compliance.

Recommendations for nutrition interventions with overweight African-American adolescents and young adults at the Atlanta Job Corps Center.

Focus groups were used to gain insight into the nutrition-related attitudes and motivations of overweight African-American adolescents and young adults enrolled in the Atlanta Job Corps Center in preparation for designing an effective and culturally appropriate nutrition intervention for this population. Eighteen students and 18 staff members participated in six different focus groups. Focus group themes suggest that an intervention with this target group should address overeating, proper diet composition, emotional eating, long-term consequences of a poor diet, group work, and incentives. Limiting food portions, offering healthy, appealing food choices, and displaying nutritional content of foods in the cafeteria were also suggested. It was also suggested that the intervention should be ongoing and led by someone who is patient, supportive, and has overcome an overweight problem. An intervention based on these recommendations can be specifically tailored to this target group and, potentially, be effective in changing dietary behaviors and lifestyle.

Prevalence of metabolic syndrome risk factors among young adult Asian Indians.

Metabolic syndrome has a high prevalence within the U.S population. Asian Indians have a greater prevalence of the chronic diseases associated with this syndrome compared to Caucasians. This study aimed to determine the prevalence of risk factors of metabolic syndrome in young adult Asian Indians. Behavioral risk factors, dietary intake, and anthropometric measurements were assessed on all study participants (n=50). The mean BMI was 23.2 and 20.4, waist circumference was 87 and 79 cm, and percent body fat was 16 and 26% for males and females, respectively. Macronutrient contributions to the total energy intake were: carbohydrate 55% for males and females, protein 14 and 12% for males and females respectively, and total fat 31 and 33% for males and females, respectively. Using the definition of the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, ATP III), these Asian Indians did not appear to be at high risk for developing metabolic syndrome. However, using the newly proposed recommendations for Asian Indians, the results suggest that this group may be at risk for developing metabolic syndrome.