Adaptation to cystine limitation stress promotes PDAC tumor growth and metastasis through translational upregulation of OxPPP.

Cystine/cysteine is critical for antioxidant response and sulfur metabolism in cancer cells and is one of the most depleted amino acids in the PDAC microenvironment. The effects of cystine limitation stress (CLS) on PDAC progression are poorly understood. Here we report that adaptation to CLS (CLSA) promotes PDAC cell proliferation and tumor growth through translational upregulation of the oxidative pentose phosphate pathway (OxPPP).

Stress response regulation of mRNA translation: Implications for antioxidant enzyme expression in cancer.

From tumorigenesis to advanced metastatic stages, tumor cells encounter stress, ranging from limited nutrient and oxygen supply within the tumor microenvironment to extrinsic and intrinsic oxidative stress. Thus, tumor cells seize regulatory pathways to rapidly adapt to distinct physiologic conditions to promote cellular survival, including manipulation of mRNA translation. While it is now well established that metastatic tumor cells must up-regulate their antioxidant capacity to effectively spread and that regulation of antioxidant enzymes is imperative to disease progression, relatively few studies have assessed how translation and the hijacking of RNA systems contribute to antioxidant responses of tumors.

Preventing loss of sirt1 lowers mitochondrial oxidative stress and preserves C2C12 myotube diameter in an in vitro model of cancer cachexia.

Cancer cachexia is a multifactorial syndrome associated with advanced cancer that contributes to mortality. Cachexia is characterized by loss of body weight and muscle atrophy. Increased skeletal muscle mitochondrial reactive oxygen species (ROS) is a contributing factor to loss of muscle mass in cachectic patients.

Tissue-specific expression differences in Ras-related GTP-binding proteins in male rats.

The protein kinase Mechanistic Target of Rapamycin (mTOR) in Complex 1 (mTORC1) is regulated in part by the Ras-related GTP-binding proteins (Rag GTPases). Rag GTPases form a heterodimeric complex consisting of either RagA or RagB associated with either RagC or RagD and act to localize mTORC1 to the lysosomal membrane. Until recently, RagA and RagB were thought to be functionally redundant, as were RagC and RagD.

Lower muscle protein synthesis in humans with obesity concurrent with lower expression of muscle IGF1 splice variants.

Objective: This study tested the hypothesis that expression of insulin-like growth factor 1 (IGF-1) protein and mRNA splice variants is lower in skeletal muscle of humans with obesity who have a lower mixed-muscle protein fractional synthesis rate (MMP-FSR) when compared with individuals without obesity.

Methods: The study included nine participants with obesity (OB, mean [SD],  BMI = 35 [3] kg/m , MMP-FSR = 0.06%/h [0.

Exercise Is Medicine for Nonalcoholic Fatty Liver Disease: Exploration of Putative Mechanisms.

Exercise remains a key component of nonalcoholic fatty liver disease (NAFLD) treatment. The mechanisms that underpin improvements in NAFLD remain the focus of much exploration in our attempt to better understand how exercise benefits patients with NAFLD. In this review, we summarize the available scientific literature in terms of mechanistic studies which explore the role of exercise training in modulating fatty acid metabolism, reducing hepatic inflammation, and improving liver fibrosis.

Glucose-Induced Activation of mTORC1 is Associated with Hexokinase2 Binding to Sestrins in HEK293T Cells.

Background: Sestrins (SESN1-3) act as proximal sensors in leucine-induced activation of the protein kinase mechanistic target of rapamycin (mTOR) in complex 1 (mTORC1), a key regulator of cell growth and metabolism.

Objective: In the present study, the hypothesis that SESNs also mediate glucose-induced activation of mTORC1 was tested.

Methods: Rats underwent overnight fasting, and in the morning, either saline or a glucose solution (4 g⋅kg BW/10 mL⋅kg) was administered by oral gavage; mTORC1 activation in the tibialis anterior muscle was assessed.

Serum Fibroblast Growth Factor 21 Is Markedly Decreased following Exercise Training in Patients with Biopsy-Proven Nonalcoholic Steatohepatitis.

Background And Aims: Exercise remains a key component of nonalcoholic fatty liver disease (NAFLD) treatment. However, mechanisms underpinning the improvements in NAFLD seen with exercise are unclear. Exercise improved liver fat and serum biomarkers of liver fibrosis in the NASHFit trial.

Loss of 4E-BPs prevents the hindlimb immobilization-induced decrease in protein synthesis in skeletal muscle.

The present study was designed to test the hypothesis that upregulating protein synthesis attenuates the loss of muscle mass in a model of disuse atrophy. The studies compared the effect of unilateral hindlimb immobilization in wild-type (WT) mice and double-knockout (DKO) mice lacking the translational regulators 4E-BP1 and 4E-BP2. Immobilization-induced downregulation of protein synthesis occurred in both groups of mice, but protein synthesis was higher in gastrocnemius muscle from the immobilized hindlimb of fasted DKO compared with WT mice.

An integrative approach to assessing effects of a short-term Western diet on gene expression in rat liver.

Consumption of a diet rich in saturated fatty acids and carbohydrates contributes to the accumulation of fat in the liver and development of non-alcoholic steatohepatitis (NASH). Herein we investigated the hypothesis that short-term consumption of a high fat/sucrose Western diet (WD) alters the genomic and translatomic profile of the liver in association with changes in signaling through the protein kinase mTORC1, and that such alterations contribute to development of NAFLD. The results identify a plethora of mRNAs that exhibit altered expression and/or translation in the liver of rats consuming a WD compared to a CD.

PERK/ATF4-dependent expression of the stress response protein REDD1 promotes proinflammatory cytokine expression in the heart of obese mice.

Endoplasmic reticulum (ER) stress and inflammation are hallmarks of myocardial impairment. Here, we investigated the role of the stress response protein regulated in development and DNA damage 1 (REDD1) as a molecular link between ER stress and inflammation in cardiomyocytes. In mice fed a high-fat high-sucrose (HFHS, 42% kcal fat, 34% sucrose by weight) diet for 12 wk, REDD1 expression in the heart was increased in coordination with markers of ER stress and inflammation.

Spleen Tyrosine Kinase Contributes to Müller Glial Expression of Proangiogenic Cytokines in Diabetes.

Purpose: Neuroglial dysfunction occurs early in the progression of diabetic retinopathy. In response to diabetes or hypoxia, Müller glia secrete cytokines and growth factors that contribute to disease progression. This study was designed to examine common signaling pathways activated in Müller glia by both type 1 and pre-/type 2 diabetes.

Convergence of signaling pathways in mediating actions of leucine and IGF-1 on mTORC1 in L6 myoblasts.

Leucine and insulin-like growth factor-1 (IGF-1) are important regulators of protein synthesis in skeletal muscle. The mechanistic target of rapamycin complex 1 (mTORC1) is of particular importance in their mechanism of action. In the present study, pathways through which leucine and IGF-1 converge to mediate activation of mTORC1 were examined in L6 myoblasts that were deprived of leucine and serum followed by readdition of either leucine or IGF-1.

The effect of chronic exposure to metformin in a new type-2 diabetic NONcNZO10/LtJ mouse model of stroke.

Background: Diabetes is an independent risk factor of stroke and previous studies have confirmed that diabetic patients and animals experience poorer clinical outcomes following stroke. In this study, we aim to determine the effect of chronic exposure of the first-line antidiabetic agent, metformin, to restore euglycemia and to impact brain cell death following stroke in a new type-2 diabetes, NONcNZO10/LtJ (RCS-10) mouse model of stroke.

Methods: Male RCS-10 mice received a moderate (11%) fat diet post-weaning, at 4 weeks of age, and became diabetic by 12-14 weeks, thus resembling human maturity-onset diabetes.

HuR-dependent SOD2 protein synthesis is an early adaptation to anchorage-independence.

During metastasis cancer cells must adapt to survive loss of anchorage and evade anoikis. An important pro-survival adaptation is the ability of metastatic tumor cells to increase their antioxidant capacity and restore cellular redox balance. Although much is known about the transcriptional regulation of antioxidant enzymes in response to stress, how cells acutely adapt to alter antioxidant enzyme levels is less well understood.

mTORC1 regulates high levels of protein synthesis in retinal ganglion cells of adult mice.

Mechanistic target of rapamycin (mTOR) and mTOR complex 1 (mTORC1), linchpins of the nutrient sensing and protein synthesis pathways, are present at relatively high levels in the ganglion cell layer (GCL) and retinal ganglion cells (RGCs) of rodent and human retinas. However, the role of mTORCs in the control of protein synthesis in RGC is unknown. Here, we applied the SUrface SEnsing of Translation (SUnSET) method of nascent protein labeling to localize and quantify protein synthesis in the retinas of adult mice.

Targeting Protein Translation in Melanoma by Inhibiting EEF-2 Kinase Regulates Cholesterol Metabolism though SREBP2 to Inhibit Tumour Development.

Decreasing the levels of certain proteins has been shown to be important for controlling cancer but it is currently unknown whether proteins could potentially be targeted by the inhibiting of protein synthesis. Under this circumstance, targeting protein translation could preferentially affect certain pathways, which could then be of therapeutic advantage when treating cancer. In this report, eukaryotic elongation factor-2 kinase (EEF2K), which is involved in protein translation, was shown to regulate cholesterol metabolism.

NASHFit: A randomized controlled trial of an exercise training program to reduce clotting risk in patients with NASH.

Background And Aims: NASH is a common disease associated with increased rates of thromboembolism (TE). Although exercise training can lessen thrombotic risk in patients with vascular disease, whether similar findings are observed in patients with NASH is open for study.

Approach And Results: We conducted a 20-week randomized controlled clinical trial involving patients with biopsy-confirmed NASH.