Salubrinal Enhances Cancer Cell Death during Glucose Deprivation through the Upregulation of xCT and Mitochondrial Oxidative Stress.

Cancer cells have the metabolic flexibility to adapt to heterogeneous tumor microenvironments. The integrated stress response (ISR) regulates the cellular adaptation response during nutrient stress. However, the issue of how the ISR regulates metabolic flexibility is still poorly understood. In this study, we activated the ISR using salubrinal in cancer cells and found that salubrinal repressed cell growth, colony formation, and migration but did not induce cell death in a glucose-containing condition. Under a glucose-deprivation condition, salubrinal induced cell death and increased the levels of mitochondrial reactive oxygen species (ROS). We found that these effects of salubrinal and glucose deprivation were associated with the upregulation of xCT (SLC7A11), which functions as an antiporter of cystine and glutamate and maintains the level of glutathione to maintain redox homeostasis. The upregulation of xCT did not protect cells from oxidative stress-mediated cell death but promoted it during glucose deprivation. In addition, the supplementation of ROS scavenger N-acetylcysteine and the maintenance of intracellular levels of amino acids via sulfasalazine (xCT inhibitor) or dimethyl-α-ketoglutarate decreased the levels of mitochondrial ROS and protected cells from death. Our results suggested that salubrinal enhances cancer cell death during glucose deprivation through the upregulation of xCT and mitochondrial oxidative stress.

ROS Mediate xCT-Dependent Cell Death in Human Breast Cancer Cells under Glucose Deprivation.

xCT, also known as solute carrier family 7 member 11 (SLC7A11), the light chain of the cystine/glutamate antiporter, is positively correlated with cancer progression due to antioxidant function. During glucose deprivation, the overexpression of xCT does not protect cancer cells but instead promotes cell death. Further understanding the mechanism of glucose deprivation-induced cell death is important for developing anticancer treatments targeting the glucose metabolism. In this study, we found that breast cancer cells with a high expression of xCT demonstrated increased levels of reactive oxygen species (ROS) and were more sensitive to glucose deprivation than the cells with a low expression of xCT. However, AMP-activated protein kinase (AMPK) did not significantly affect glucose-deprivation-induced cell death. The antioxidant N-acetyl-cysteine prevented glucose-deprivation-induced cell death, and the glutathione biosynthesis inhibitor L-buthionine-S, R-sulfoximine enhanced glucose-deprivation-induced cell death. The inhibition of xCT by sulfasalazine or a knockdown of xCT reduced the glucose-deprivation-increased ROS levels and glucose-deprivation-induced cell death. Glucose deprivation reduced the intracellular glutamate, and supplementation with α-ketoglutarate prevented the glucose-deprivation-increased ROS levels and rescued cell death. The knockdown of sirtuin-3 (SIRT3) further enhanced the ROS levels, and promoted xCT-related cell death after glucose deprivation. In conclusion, our results suggested that ROS play a critical role in xCT-dependent cell death in breast cancer cells under glucose deprivation.

Correction to: Individualized home-based exercise and nutrition interventions improve frailty in older adults: a randomized controlled trial.

Following publication of the original article [1], the author reported that an abbreviation was incorrect in the original article.

Individualized home-based exercise and nutrition interventions improve frailty in older adults: a randomized controlled trial.

BACKGROUND: Frail older adults are predisposed to multiple comorbidities and adverse events. Recent interventional studies have shown that frailty can be improved and managed. In this study, effective individualized home-based exercise and nutrition interventions were developed for reducing frailty in older adults. METHODS: This study was a four-arm, single-blind, randomized controlled trial conducted between October 2015 and June 2017 at Miaoli General Hospital in Taiwan. Overall, 319 pre-frail or frail older adults were randomly assigned into one of the four study groups (control, exercise, nutrition, and exercise plus nutrition [combination]) and followed up during a 3-month intervention period and 3-month self-maintenance period. Improvement in frailty scores was the primary outcome. Secondary outcomes included improvements in physical performance and mental health. The measurements were performed at baseline, 1 month, 3 months, and 6 months. RESULTS: At the 6-month measurement, the exercise (difference in frailty score change from baseline: - 0.23; 95% confidence interval [CI]: - 0.41, - 0.05; p = 0.012), nutrition (- 0.28; 95% CI: - 0.46, - 0.11; p = 0.002), and combination (- 0.34; 95% CI: - 0.52, - 0.16; p <  0.001) groups exhibited significantly greater improvements in the frailty scores than the control group. Significant improvements were also observed in several physical performance parameters in the exercise, nutrition, and combination groups, as well as in the 12-Item Short Form Health Survey mental component summary score for the nutrition group. CONCLUSIONS: The designated home-based exercise and nutrition interventions can help pre-frail or frail older adults to improve their frailty score and physical performance. TRIAL REGISTRATION: Retrospectively registered at ClinicalTrials.gov (identifier: NCT03477097); registration date: March 26, 2018.

Dietary education with customised dishware and food supplements can reduce frailty and improve mental well-being in elderly people: A single-blind randomized controlled study.

BACKGROUND AND OBJECTIVES: The elderly population is increasing rapidly worldwide, and frailty is a common geriatric syndrome. Comprehensive dietary management strategies may have beneficial effects on frailty prevention and reversal. This 3-month single-blind, paralleled, randomized controlled trial compared the effects of micronutrients and/or protein supplements, and a personalised diet on frailty status in elderly individuals. METHODS AND STUDY DESIGN: Between 2014 and 2015, 40 prefrail or frail subjects aged >=65 years were recruited at Miaoli General Hospital, Taiwan. Of these, 37 completed the study, and 36 were included in the analysis. Participants were randomly assigned to one of four treatment groups: (1) the control (2) multiple micronutrient supplements, (3) multiple micronutrients plus isolated soy protein supplement, and (4) individualised nutrition education with customised dishware and food supplements (mixed nuts and skimmed milk powder). Dietary intake, protein biomarkers, frailty score, and geriatric depression score were assessed. RESULTS: Individualised nutrition education with customised dishware and food supplements significantly increased the participants' intake of vegetables, dairy, and nuts, in addition to increasing the concentration of urinary urea nitrogen. It yielded a significant reduction in frailty score (p<0.05) and a borderline reduction (p=0.063) in geriatric depression score. No significant beneficial changes were observed for the other two intervention groups. CONCLUSIONS: Our study indicated that a dietary approach with easy-to-comprehend dishware and food supplements to optimize the distribution of the consumption of six food groups improved frailty status and, potentially, psychological well-being in elderly people.

Dietary Pattern Associated with Frailty: Results from Nutrition and Health Survey in Taiwan.

OBJECTIVES: To investigate whether dietary patterns are associated with frailty phenotypes in an elderly Taiwanese population. DESIGN: Cross-sectional. SETTING: Nutrition and Health Survey in Taiwan (NAHSIT), 2014-2016. PARTICIPANTS: Noninstitutionalized Taiwanese nationals aged 65 years and older enrolled in the NAHSIT (N = 923). MEASUREMENTS: Dietary intake was assessed using a 79-item food-frequency questionnaire (FFQ). Presence of 5 frailty phenotypes was determined using modified Fried criteria and are summed into a frailty score. Using data from the NAHSIT (2014-15), reduced rank regression was used to find a dietary pattern that explained maximal degree of variation of the frailty scores. Logistic regression models were used to estimate the association between frailty and dietary pattern. The findings were validated with data from 2016. RESULTS: The derived dietary pattern was characterized with a high consumption of fruit, nuts and seeds, tea, vegetables, whole grains, shellfish, milk, and fish. The prevalence of frailty was 7.8% and of prefrailty was 50.8%, defined using the modified Fried criteria. Using data from the NAHSIT (2014-15), the dietary pattern score showed an inverse dose-response relationship with prevalence of frailty and pre-frailty. Individuals in the second dietary pattern tertile were one-third as likely to be frail as those in the first tertile (adjusted odds ratio (aOR) = 0.32, 95% confidence interval (CI) = 0.12-0.85), and those in the third tertile were 4% as likely to be frail as those in the first tertile (aOR = 0.04, 95% CI = 0.01-0.18). The dietary pattern score estimated using FFQ data from the NAHSIT 2016 was also significantly and inversely associated with frailty. CONCLUSION: Individuals with a dietary pattern with more phytonutrient-rich plant foods, tea, omega-3-rich deep-sea fish, and other protein-rich foods such as shellfish and milk had a reduced prevalence of frailty. Further research is necessary to confirm these findings and investigate whether related dietary interventions can reduce frailty in older adults.