bims-stacyt 2022-06-19 papers

J Exp Clin Cancer Res. 2022 Jun 14. 41(1): 203

The pleiotropic roles of adipocyte secretome in remodeling breast cancer.

Xiaomei Zhou, Jun Zhang, Wenchang Lv, Chongru Zhao, Yu Xia, Yiping Wu, Qi Zhang.

BACKGROUND: Breast cancer is the leading female cancer type and the cause of cancer-related mortality worldwide. Adipocytes possess important functions of energy supply, metabolic regulation, and cytokine release, and are also the matrix cell that supports mammary gland tissue. In breast cancer tumor microenvironment (TME), adipocytes are the prominent stromal cells and are implicated in inflammation, metastatic formation, metabolic remodeling, and cancer susceptibility.
MAIN BODY: It is well-established that adipocyte secretome is a reservoir engaged in the regulation of tumor cell behavior by secreting a large number of cytokines (IL-6, IL-8, and chemokines), adipokines (leptin, adiponectin, autotaxin, and resistin), lipid metabolites (free fatty acids and β-hydroxybutyrate), and other exosome-encapsulated substances. These released factors influence the evolution and clinical outcome of breast cancer through complex mechanisms. The progression of breast cancer tumors revolves around the tumor-adipose stromal network, which may contribute to breast cancer aggressiveness by increasing the pro-malignant potential of TME and tumor cells themselves. Most importantly, the secretome alterations of adipocytes are regarded as distinctly important targets for breast cancer diagnosis, treatment, and drug resistance.
CONCLUSION: Therefore, this review will provide a comprehensive description of the specific adipocyte secretome characteristics and interactions within TME cell populations, which will enable us to better tailor strategies for tumor stratification management and treatment.

Keywords: Adipocytes; Adipokines; Breast cancer; Cytokines; Immune regulation; Secretome

DOI: https://doi.org/10.1186/s13046-022-02408-z

Cell Biochem Biophys. 2022 Jun 14.

Metabolite Effect on Angiogenesis: Insights from Transcriptome Analysis.

P Sunitha, Kesavan R Arya, Achuthsankar S Nair, Oommen V Oommen, Perumana R Sudhakaran.

Metabolic status of the cells is important in the expression of the angiogenic phenotype in endothelial cells. Our earlier studies demonstrated the effects of metabolites such as lactate, citrate and lipoxygenase products, on VEGFA-VEGFR2 signaling pathway. Though this link between metabolite status and molecular mechanisms of angiogenesis is becoming evident, it is not clear how it affects genome-level expression in endothelial cells, critical to angiogenesis. In the present study, computational analysis was carried out on the transcriptome data of 4 different datasets where HUVECs were exposed to low and high glucose, both in vitro and in vivo, and the expression of a key enzyme involved in glucose metabolism is altered. The differentially expressed genes belonging to both VEGFA-VEGFR2 signaling pathway, as well as several VEGF signature genes as hub genes were also identified. These findings suggest the metabolite dependence, particularly glucose dependence, of angiogenesis, involving modulation of genome-level expression of angiogenesis- functional genome. This is important in tumor angiogenesis where reprogramming of metabolism is critical.

Keywords: Angiogenesis; Differentially expressed genes; Endothelial cells; Glucose; Metabolite; VEGF responsive signature genes

DOI: https://doi.org/10.1007/s12013-022-01078-0

Endocr Connect. 2022 Jun 01. pii: EC-22-0054. [Epub ahead of print]

Sex-specific modulation of circulating growth differentiation factor-15 in patients with type 2 diabetes and/or obesity.

Mohamed Asrih, Flore Sinturel, Richard Dubos, Idris Guessous, Zoltan Pataky, Charna Dibner, François R Jornayvaz, Karim Gariani.

OBJECTIVE: Growth differentiation factor-15 (GDF15), a key metabolic regulator, is associated with obesity and diabetes in which sex-specific differences have been reported. Thus, we assessed whether GDF15 could be dependent on sex in diabetes and/or obesity groups.
METHODS: We measured serum GDF15 levels by ELISA in eight lean women and men (N = 16), eight women and eight men having obesity (N = 16), eight women and eight men with type 2 diabetes (T2D, N = 16), and seven women and nine men with both diabetes and obesity (N = 16). Estimation of the difference in the means of each group was performed by two-way ANOVA. The interdependence of the different variates was addressed by multivariate analysis. Correlations between GDF15 levels and HOMA-IR, HbA1c, triglycerides, HDL, and LDL were explored by linear regression.
RESULTS: Being a woman and having obesity alone or with diabetes decreased GDF15 serum levels (β = -0.47, CI = [-0.95, 0.00], p = 0.052; β = -0.45, (β = -0.45, CI = [-0.94, 0.05], p = 0.075). Diabetes independently of metformin treatment and obesity was not predictive of low GDF15 levels (β = 0.10, CI = [-0.36, 0.57], p = 0.7). Correlation analysis showed that HOMA-IR (r = 0.45, p = 0.008) and triglycerides (r = 0.41, p = 0.017) were positively and HDL (r = -0.48, p = 0.005), negatively correlated with GDF15 levels in men.
CONCLUSIONS/INTERPRETATION: GDF15 level was significantly different between men and women, as well as between the groups. Sex-group interaction revealed that being a woman and having obesity alone or in combination with diabetes decreased GDF15 levels.

DOI: https://doi.org/10.1530/EC-22-0054

EMBO Rep. 2022 Jun 13. e54226

GM-CSF suppresses antioxidant signaling and drives IL-1β secretion through NRF2 downregulation.

Sara Di Carlo, Georg Häcker, Ian E Gentle.

GM-CSF is a potent inflammatory cytokine regulating myeloid cell differentiation, hematopoiesis, and various other functions. It is functionally associated with a number of inflammatory pathologies including rheumatoid arthritis and inflammatory bowel disease. GM-CSF has been found to promote NLRP3-dependent IL-1β secretion, which may have a significant role in driving inflammatory pathologies. However, the molecular mechanisms remain unknown. Here, we show that GM-CSF induces IL-1β secretion through a ROS-dependent pathway. TNF is required for reactive oxygen species (ROS) generation that strikingly does not promote NLRP3 activation, but instead drives ubiquitylation of IL-1β, promoting its cleavage through basal NRLP3 activity. GM-CSF regulates this pathway through suppression of antioxidant responses via preventing upregulation of NRF2. Thus, the pro-inflammatory effect of GM-CSF on IL-1β is through suppression of antioxidant responses, which leads to ubiquitylation of IL-1β and enhanced processing. This study highlights the role of metabolic regulation of inflammatory signaling and reveals a novel mechanism for GM-CSF to promote inflammation.

Keywords: GM-CSF; IL-1β; NRF2; TNF; inflammasome

DOI: https://doi.org/10.15252/embr.202154226

FASEB J. 2022 07;36(7): e22396

Activation and execution of the hepatic integrated stress response by dietary essential amino acid deprivation is amino acid specific.

William O Jonsson, Emily T Mirek, Ronald C Wek, Tracy G Anthony.

Dietary removal of an essential amino acid (EAA) triggers the integrated stress response (ISR) in liver. Herein, we explored the mechanisms that activate the ISR and execute changes in transcription and translation according to the missing EAA. Wild-type mice and mice lacking general control nonderepressible 2 (Gcn2) were fed an amino acid complete diet or a diet devoid of either leucine or sulfur amino acids (methionine and cysteine). Serum and liver leucine concentrations were significantly reduced within the first 6 h of feeding a diet lacking leucine, corresponding with modest, GCN2-dependent increases in Atf4 mRNA translation and induction of selected ISR target genes (Fgf21, Slc7a5, Slc7a11). In contrast, dietary removal of the sulfur amino acids lowered serum methionine, but not intracellular methionine, and yet hepatic mRNA abundance of Atf4, Fgf21, Slc7a5, Slc7a11 substantially increased regardless of GCN2 status. Liver tRNA charging levels did not correlate with intracellular EAA concentrations or GCN2 status and remained similar to mice fed a complete diet. Furthermore, loss of Gcn2 increased the occurrence of ribosome collisions in liver and derepressed mechanistic target of rapamycin complex 1 signal transduction, but these changes did not influence execution of the ISR. We conclude that ISR activation is directed by intracellular EAA concentrations, but ISR execution is not. Furthermore, a diet devoid of sulfur amino acids does not require GCN2 for the ISR to execute changes to the transcriptome.

Keywords: dietary restriction; feeding; mammalian; polysomes; postprandial period; protein synthesis

DOI: https://doi.org/10.1096/fj.202200204RR