A non-catalytic scaffolding activity of hexokinase 2 contributes to EMT and metastasis.

Hexokinase 2 (HK2), which catalyzes the first committed step in glucose metabolism, is induced in cancer cells. HK2's role in tumorigenesis has been attributed to its glucose kinase activity. Here, we describe a kinase independent HK2 activity, which contributes to metastasis.

CD36-Mediated Metabolic Rewiring of Breast Cancer Cells Promotes Resistance to HER2-Targeted Therapies.

Although it is established that fatty acid (FA) synthesis supports anabolic growth in cancer, the role of exogenous FA uptake remains elusive. Here we show that, during acquisition of resistance to HER2 inhibition, metabolic rewiring of breast cancer cells favors reliance on exogenous FA uptake over de novo FA synthesis. Through cDNA microarray analysis, we identify the FA transporter CD36 as a critical gene upregulated in cells with acquired resistance to the HER2 inhibitor lapatinib.

Perspectives from the Kidney Health Initiative on Advancing Technologies to Facilitate Remote Monitoring of Patient Self-Care in RRT.

Telehealth and remote monitoring of a patient's health status has become more commonplace in the last decade and has been applied to conditions such as heart failure, diabetes mellitus, hypertension, and chronic obstructive pulmonary disease. Conversely, uptake of these technologies to help engender and support home RRTs has lagged. Although studies have looked at the role of telehealth in RRT, they are small and single-centered, and both outcome and cost-effectiveness data are needed to inform future decision making.

Targeting Access to Kidney Care Via Telehealth: The VA Experience.

The Veterans Affairs (VA) is the largest integrated health care system in the United States and is responsible for the care of a population with a disproportionately high rate of CKD. As such, ensuring access to kidney health services is a VA imperative. One facet of the VA's strategy to reduce CKD is to leverage the use of teletechnology to expand the VA's outreach to Veterans with kidney disease.

Chronic Kidney Disease Progression and Cardiovascular Outcomes Following Cardiac Catheterization-A Population-Controlled Study.

Background: Studies of kidney disease associated with cardiac catheterization typically rely on billing records rather than laboratory data. We examined the associations between percutaneous coronary interventions, acute kidney injury, and chronic kidney disease progression using comprehensive Veterans Affairs clinical and laboratory databases.

Methods And Results: Patients undergoing percutaneous coronary interventions between 2005 and 2010 (N=24 405) were identified in the Veterans Affairs Clinical Assessment, Reporting, and Tracking registry and examined for associated acute kidney injury and chronic kidney disease development or progression relative to 24 405 matched population controls.

Designing a broad-spectrum integrative approach for cancer prevention and treatment.

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis.

Metabolic reprogramming and dysregulated metabolism: cause, consequence and/or enabler of environmental carcinogenesis?

Environmental contributions to cancer development are widely accepted, but only a fraction of all pertinent exposures have probably been identified. Traditional toxicological approaches to the problem have largely focused on the effects of individual agents at singular endpoints. As such, they have incompletely addressed both the pro-carcinogenic contributions of environmentally relevant low-dose chemical mixtures and the fact that exposures can influence multiple cancer-associated endpoints over varying timescales.

Cyclical dehydration-induced renal injury and Mesoamerican nephropathy: as sweet by any other name?

Severe cyclical dehydration induces chronic renal injury in rodents. This effect is attenuated by global fructokinase deficiency, suggesting possible roles for fructokinase and fructose metabolism in mediating or promoting dehydration-induced injury. Clinical and pathological similarities between this injury model and endemic Mesoamerican nephropathy (MeN) have fueled speculation that dehydration-induced injury and MeN may share common mechanistic underpinnings involving fructokinase that can be targeted to mitigate disease development, progression, and/or severity.

Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer.

Accelerated glucose metabolism is a common feature of cancer cells. Hexokinases catalyze the first committed step of glucose metabolism. Hexokinase 2 (HK2) is expressed at high level in cancer cells, but only in a limited number of normal adult tissues.

Peptides modeled on the RGG domain of AUF1/hnRNP-D regulate 3' UTR-dependent gene expression.

Messenger RNA binding proteins control post-transcriptional gene expression of targeted mRNAs. The RGG (arginine-glycine-glycine) domain of the AUF1/hnRNP-D mRNA binding protein is a regulatory region that is essential for protein function. The AUF1-RGG peptide, modeled on the RGG domain of AUF1, represses expression of the macrophage cytokine, VEGF.

AUF1/hnRNP D represses expression of VEGF in macrophages.

Vascular endothelial growth factor (VEGF) is a regulator of vascularization in development and is a key growth factor in tissue repair. In disease, VEGF contributes to vascularization of solid tumors and arthritic joints. This study examines the role of the mRNA-binding protein AUF1/heterogeneous nuclear ribonucleoprotein D (AUF1) in VEGF gene expression.

Hexokinase: a novel sugar kinase coupled to renal epithelial cell survival.

Hexokinases have emerged as novel mediators of the antiapoptotic effects of growth factors in a wide variety of cells. These effects have been attributed to highly regulated direct physical and functional interactions with mitochondria. The demonstration that mitochondrial hexokinases can prevent apoptogenic 'Bax attack' in proximal tubule cells suggests a need to reexamine the specific contributions of hexokinases and glucose metabolism in this nephron segment and elsewhere within the kidney.

mTORC1 hyperactivity inhibits serum deprivation-induced apoptosis via increased hexokinase II and GLUT1 expression, sustained Mcl-1 expression, and glycogen synthase kinase 3beta inhibition.

The current concept is that Tsc-deficient cells are sensitized to apoptosis due to the inhibition of Akt activity by the negative feedback mechanism induced by the hyperactive mTORC1. Unexpectedly, however, we found that Tsc1/2-deficient cells exhibit increased resistance to serum deprivation-induced apoptosis. mTORC1 hyperactivity contributes to the apoptotic resistance of serum-deprived Tsc1/2-deficient cells in part by increasing the growth factor-independent expression of hexokinase II (HKII) and GLUT1.

Reduced susceptibility to azoxymethane-induced aberrant crypt foci formation and colon cancer in growth hormone deficient rats.

Objectives: To evaluate the role of GH in colon carcinogenesis, we examined the formation of aberrant crypt foci (ACFs) and tumor development in wild type (WT) and GH-deficient, spontaneous dwarf rats (SDRs) exposed to the carcinogen azoxymethane (AOM).

Design: ACF were quantified by stereomicroscopy and tumor number and weights were recorded for each animal. Cell proliferation was measured by vincristine metaphase arrest, flow cytometry, and bromodeoxyuridine (BrdU) incorporation.

Is Akt the "Warburg kinase"?-Akt-energy metabolism interactions and oncogenesis.

The serine/threonine kinase Akt - also known as protein kinase B (PKB) - has emerged as one of the most frequently activated protein kinases in human cancer. In fact, most, if not all, tumors ultimately find a way to activate this important kinase. As such, Akt activation constitutes a hallmark of most cancer cells, and such ubiquity presumably connotes important roles in tumor genesis and/or progression.

Functional polymorphism of the Anpep gene increases promoter activity in the Dahl salt-resistant rat.

We have reported that aminopeptidase N/CD13, which metabolizes angiotensin III to angiotensin IV, exhibits greater renal tubular expression in the Dahl salt-resistant (SR/Jr) rat than its salt-sensitive (SS/Jr) counterpart. In this work, aminopeptidase N (Anpep) genes from SS/Jr and SR/Jr strains were compared. The coding regions contained only silent single nucleotide polymorphisms between strains.

Mitochondrial hexokinases: guardians of the mitochondria.

There is accumulating evidence that cell survival and energy metabolism are inexorably linked. As a major mediator of both the metabolic and anti-apoptotic effects of growth factors, the serine/threonine kinase Akt (also known as protein kinase B or PKB) is particularly well-suited to coordinate the regulation of these interrelated processes. Recent demonstrations that growth factors and Akt require glucose (Glc) to prevent apoptosis and promote cell survival are compatible with this contention, as is a positive correlation between Akt-regulated mitochondrial hexokinase (mtHK) association and apoptotic resistance.