Leucine supplementation differentially enhances pancreatic cancer growth in lean and overweight mice

Kristyn A Liu1†, Laura M Lashinger1†, Audrey J Rasmussen1† and Stephen D Hursting12* Author Affiliations 1 Department of Nutritional Sciences, University of Texas at Austin, Austin, TX 78723, USA 2 Department of Molecular Carcinogenesis, University of Texas M.D. Anderson Cancer Center, 1808 Park Road 1c, Smithville, TX 78957, USABackground: The risk of pancreatic cancer, the 4th deadliest cancer for both men and women in the United States, is increased by obesity. Calorie restriction (CR) is a well-known dietary regimen that prevents or reverses obesity and suppresses tumorigenesis in a variety of animal models, at least in part via inhibition of mammalian target of rapamycin (mTOR) signaling. Branched-chain amino acids (BCAA), especially leucine, activate mTOR and enhance growth and proliferation of myocytes and epithelial cells, which is why leucine is a popular supplement among athletes. Leucine is also increasingly being used as a treatment for pancreatic cancer cachexia, but the effects of leucine supplementation on pancreatic tumor growth have not been elucidated. Results: Supplementation with leucine increased pancreatic tumor growth in both lean (104 ± 17 mm3 versus 46 ± 13 mm3; P <0.05) and overweight (367 ± 45 mm3 versus 230 ± 39 mm3; P <0.01) mice, but tumor enhancement was associated with different biological outcomes depending on the diet. In the lean mice, leucine increased phosphorylation of mTOR and downstream effector S6 ribosomal protein, but in the overweight mice, leucine reduced glucose clearance and thus increased the amount of circulating glucose available to the tumor. Conclusion: These findings show that leucine supplementation enhances tumor growth in both lean and overweight mice through diet-dependent effects in a murine model of pancreatic cancer, suggesting caution against the clinical use of leucine supplementation for the purposes of skeletal muscle enhancement in cachectic patients.Nutritional Science

A Review: Examining Narcissism in Eating Disorders: The Relationship Between Two Types of Eating Disorders—Anorexia Nervosa and Bulimia Nervosa—and Two Forms of Narcissism

This research investigates the relationship between narcissism and eating disorders (EDs). Two forms of narcissism are studied, as each are present in the individual (O’Brien, 1987). The first form, core narcissism, is major, and refers to the way the individual views themselves while the second form, narcissistic defenses, are minor, serving only to protect the sense of self (Waller et al., 2006; O’Brien, 1987). Core narcissism is exhibited as grandiose or vulnerable narcissism where grandiose includes feelings of entitlement and high self-esteem while vulnerable includes low self-esteem and self-criticality (Maples et al., 2011). The narcissistic defenses can be displayed as poisonous pedagogy (“bad you”) or narcissistically abused (“poor me”) (O’Brien, 1987). Furthermore, the eating disorders studied were the second and third most common eating disorders, anorexia nervosa and bulimia nervosa, respectively (National Institute of Mental Health, 2017). Within anorexia nervosa, both the binge-purge type and restricting type were included. This study was conducted as a review of studies and scholarly articles. The specific question asked within this review is: does a correlation exist between the two forms of narcissism, core narcissism and narcissistic defenses, and anorexia nervosa or bulimia nervosa? This study thus concluded that there is a positive association between those with an eating disorder and high levels of narcissism. Specifically, there is a clear correlation of vulnerable narcissism to eating disorders, and bulimia nervosa is the eating disorder most strongly linked to high narcissism levels

Metformin and Rapamycin Reduce Pancreatic Cancer Growth in Obese Prediabetic Mice by Distinct MicroRNA-Regulated Mechanisms

Metformin treatment is associated with a decreased risk and better prognosis of pancreatic cancer (PC) in patients with type 2 diabetes, but the mechanism of metformin’s PC growth inhibition in the context of a prediabetic state is unknown. We used a Panc02 pancreatic tumor cell transplant model in diet-induced obese (DIO) C57BL/6 mice to compare the effects of metformin and the direct mammalian target of rapamycin (mTOR) inhibitor rapamycin on PC growth, glucose regulation, mTOR pathway signaling, and candidate microRNA (miR) expression. In DIO/prediabetic mice, metformin and rapamycin significantly reduced pancreatic tumor growth and mTOR-related signaling. The rapamycin effects centered on decreased mTOR-regulated growth and survival signaling, including increased expression of let-7b and cell cycle–regulating miRs. Metformin (but not rapamycin) reduced glucose and insulin levels and expression of miR-34a and its direct targets Notch, Slug, and Snail. Metformin also reduced the number and size of Panc02 tumor spheres in vitro and inhibited the expression of Notch in spheroids. Our results suggest that metformin and rapamycin can both inhibit pancreatic tumor growth in obese, prediabetic mice through shared and distinct mechanisms. Metformin and direct mTOR inhibitors, alone or possibly in combination, represent promising intervention strategies for breaking the diabetes-PC link

Starving cancer from the outside and inside: separate and combined effects of calorie restriction and autophagy inhibition on Ras-driven tumors

Abstract Background Calorie restriction (CR) prevents obesity and exerts anticancer effects in many preclinical models. CR is also increasingly being used in cancer patients as a sensitizing strategy prior to chemotherapy regimens. While the beneficial effects of CR are widely accepted, the mechanisms through which CR affects tumor growth are incompletely understood. In many cell types, CR and other nutrient stressors can induce autophagy, which provides energy and metabolic substrates critical for cancer cell survival. We hypothesized that limiting extracellular and intracellular substrate availability by combining CR with autophagy inhibition would reduce tumor growth more effectively than either treatment alone. Results A 30 % CR diet, relative to control diet, in nude mice resulted in significant decreases in body fat, blood glucose, and serum insulin, insulin-like growth factor-1, and leptin levels concurrent with increased adiponectin levels. In a xenograft model in nude mice involving H-RasG12V-transformed immortal baby mouse kidney epithelial cells with (Atg5 +/+ ) and without (Atg5 −/−) autophagic capacity, the CR diet (relative to control diet) genetically induced autophagy inhibition and their combination, each reduced tumor development and growth. Final tumor volume was greatest for Atg5 +/+ tumors in control-fed mice, intermediate for Atg5 +/+ tumors in CR-fed mice and Atg5 −/− tumors in control-fed mice, and lowest for Atg5 −/− tumors in CR mice. In Atg5 +/+ tumors, autophagic flux was increased in CR-fed relative to control-fed mice, suggesting that the prosurvival effects of autophagy induction may mitigate the tumor suppressive effects of CR. Metabolomic analyses of CR-fed, relative to control-fed, nude mice showed significant decreases in circulating glucose and amino acids and significant increases in ketones, indicating CR induced negative energy balance. Combining glucose deprivation with autophagy deficiency in Atg5 −/− cells resulted in significantly reduced in vitro colony formation relative to glucose deprivation or autophagy deficiency alone. Conclusions Combined restriction of extracellular (via CR in vivo or glucose deprivation in vitro) and intracellular (via autophagy inhibition) sources of energy and nutrients suppresses Ras-driven tumor growth more effectively than either CR or autophagy deficiency alone. Interventions targeting both systemic energy balance and tumor-cell intrinsic autophagy may represent a novel and effective anticancer strategy

Perspectives from Caregivers for Children with Retinoblastoma: Psychosocial Concerns and Genetic Counseling

Caregivers play a vital role in the care of children affected with retinoblastoma as most cases are diagnosed before the age of five years old. While previous studies have explored the psychosocial needs of caregivers of children with pediatric cancer, these have not specifically focused on retinoblastoma in the United States (US). Prior research identified the profound emotional burden in terms of depression, anxiety, guilt, isolation, and loneliness experienced by caregivers. Given previous findings and the National Cancer Institute’s recommendation for genetic counseling and testing for all individuals affected with retinoblastoma, this study aimed to assess psychosocial concerns in relation to genetic counseling specific to retinoblastoma caregivers in the US. An online questionnaire was distributed to social media support groups for current and past caregivers to a child with retinoblastoma to assess experiences in retinoblastoma care and psychosocial distress via free-response questions, multiple choice questions, and validated scales (GAD-7, PHQ-9, GSQ-8, and the Three-Item Loneliness Scale). A total of 57 responses were analyzed and the results suggest retinoblastoma caregivers in the US experience mild anxiety (GAD-7 M=7.6, SD=6.3), depression (PHQ-9 M=5.5, SD=5.6), guilt (GSQ-8 M=5.0, SD=1.8), and loneliness (Three-Item Loneliness Scale M=5.4, SD=5.7). Notably, those who met with a genetic after treatment exhibited the lowest levels of anxiety (GAD-7=1.5) and depression (PHQ-9=1.25). Conversely, those who sought genetic counseling during treatment reported highest anxiety scores (GAD-7 =8.8) and those who had multiple genetic counseling sessions showed the highest average depression scores (PHQ=7.25). While caregivers found genetic counselors and other healthcare providers to provide overall helpful support, caregiver concerns were still evidenced. Concerns centered around risks for future cancers, other health risks, interpersonal relationships, lifestyle implications, unsuitable timing of genetic counseling appointments, and limited information on medical and emotional management. Data from this study suggests genetic counselors for retinoblastoma families should strive to provide more accessible support groups, proactive discussion of possible emotional difficulties, and opportunity for more follow-up appointments. This study supports related findings that there is a significant psychological burden in US retinoblastoma caregivers and gaps in current genetic counseling practice and healthcare

Bortezomib modulates TRAIL sensitivity in human bladder and prostate cancer

Tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is a member of the TNF superfamily of cytokines that can induce cell death through engagement of cognate death receptors. Unlike other death receptor ligands, it selectively kills tumor cells while sparing normal cells. Preclinical studies in non-human primates have generated much enthusiasm regarding its therapeutic potential. However, many human cancer cell lines exhibit significant resistance to TRAIL-induced apoptosis, and the molecular mechanisms underling this are controversial. Possible explanations are typically cell-type dependent, but include alterations of receptor expression, enhancement of pro-apoptotic intracellular signaling molecules, and reductions in anti-apoptotic proteins. We show here that the proteasome inhibitor bortezomib (Velcade, PS-341) produces synergistic apoptosis in both bladder and prostate cancer cell lines within 4-6 hours when co-treated with recombinant human TRAIL which is associated with accumulation of p21 and cdk1/2 inhibition. Our data suggest that bortezomib\u27s mechanism of action involves a p21-dependent enhancement of caspase maturation. Furthermore, we found enhanced tumor cell death in in vivo models using athymic nude mice. This is associated with increases in caspase-8 and caspase-3 cleavage as well as significant reductions in microvessel density (MVD) and proliferation. Although TRAIL alone had less of an effect, its biological significance as a single agent requires further investigations. Toxicity studies reveal that the combination of bortezomib and rhTRAIL has fatal consequences that can be circumvented by altering treatment schedules. Based on our findings, we conclude that this strategy has significant therapeutic potential as an anti-cancer agent