bims-stacyt 2021-08-22 papers

Pathol Res Pract. 2021 Aug 04. pii: S0344-0338(21)00241-7. [Epub ahead of print]225 153580

OGT regulated O-GlcNacylation promotes migration and invasion by activating IL-6/STAT3 signaling in NSCLC cells.

Xin Ge, Xiao Peng, Mengmeng Li, Feng Ji, Jinliang Chen, Dongmei Zhang.

BACKGROUND: O-linked β-N-acetylglucosamine transferase (O-GlcNAc transferase, OGT) is a key enzyme that regulates O-GlcNAc modification, which is significantly up-regulated and participates in the regulation of tumorigenesis. Although previous research indicated that OGT promotes epithelial-mesenchymal transition (EMT) of lung cancer, the underlying molecular mechanisms, especially within the tumor inflammatory microenvironment, require further elucidation.
METHODS: The role of the inflammatory signaling Interleukin 6/Signal Transducer and activator of transcription 3 (IL-6/STAT3) in Non-small cell lung cancer (NSCLC) cells A549 were confirmed by Transwell assay, Scratch wound healing assay, Western blot, Immunofluorescence staining, and Nuclear and cytoplasmic extraction experiment. Western blot detected OGT expression and whole protein O-GlcNacylation after IL-6 stimulation in NSCLCs cells. The biological effects and related mechanism of OGT in NSCLC cells were investigated by Western blot, Transwell assay, Immunofluorescence staining and Immunoprecipitation. The up-stream mechanism of OGT expression was explored by employing the specific chemical inhibitors, and the expression and distribution of OGT and phosphorylated STAT3 in NSCLC samples were confirmed by immunohistochemical analysis.
RESULTS: IL-6/STAT3 promoted the migration and invasion of NSCLC cells. IL-6 stimulation elevated OGT expression and the total protein O-GlcNacylation in A549 cells. Silencing OGT by shRNA significantly inhibited the IL-6 induced EMT marker (N-cadherin and Slug) expression, migration and invasion in A549 cells. OGT interacted with and mediated O-GlcNacylation of STAT3, which promoted STAT3 Y705 phosphorylation in IL-6 treated NSCLC cells. OGT expression was positively regulated by NF-κB p65 signaling pathway after IL-6 stimulation, instead of STAT3 signaling. OGT and phosphorylated STAT3 had an obviously higher expression in human NSCLC tissues, and phosphorylated STAT3 was mainly expressed in the nucleus.
CONCLUSION: The above results showed that OGT regulated O-GlcNacylation promoted migration and invasion by activating IL-6/STAT3 signaling in lung cancer.

Keywords: EMT; IL-6/STAT3; Lung cancer; NF-κB p65; O-GlcNacylation; OGT

DOI: https://doi.org/10.1016/j.prp.2021.153580

Hum Immunol. 2021 Aug 16. pii: S0198-8859(21)00170-1. [Epub ahead of print]

Roles and Regulation of Growth differentiation factor-15 in the Immune and tumor microenvironment.

Rathna Silviya Lodi, Bin Yu, Lin Xia, Fang Liu.

Growth differentiation factor-15 (GDF-15), a member of the TGF-β superfamily, plays multiple roles in a wide variety of cellular processes. It is expressed at low levels under normal conditions but is highly expressed in tumor and tumor microenvironment (TME)-related cells, such as fibroblasts and immune cells. The TME consists of the noncancerous cells present in the tumor, including immune cells, fibroblasts, blood vessel signaling molecules and extracellular matrix, which play a key role in tumor development. GDF-15 affects both stromal cells and immune cells in the TME. It also acts on immune checkpoints, such as PD-1/PDL-1 that regulate stemness of cancer cells, indicating that GDF-15 plays a prominent role in cancer, exhibiting both protumorigenic and antitumorigenic effects, although the latter are reported much less often than the former. The present review addresses novel ideas regarding communication between GDF-15 and stromal cells, immune cells, and cancer cells in the TME. In addition, it discusses the possibility of GDF-15's clinical application as a diagnostic biomarker and therapeutic target in cancer.

Keywords: Clinical applications; Growth differentiation factor-15; Immune cells; Noncancerous cells; Tumour microenvironment

DOI: https://doi.org/10.1016/j.humimm.2021.06.007

Front Immunol. 2021 ;12 713989

Pathogenetic Interplay Between IL-6 and Tryptophan Metabolism in an Experimental Model of Obesity.

Giada Mondanelli, Elisa Albini, Elena Orecchini, Maria Teresa Pallotta, Maria Laura Belladonna, Giovanni Ricci, Ursula Grohmann, Ciriana Orabona.

Obesity is a metabolic disease characterized by a state of chronic, low-grade inflammation and dominated by pro-inflammatory cytokines such as IL-6. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that catalyzes the first step in the kynurenine pathway by transforming l-tryptophan (Trp) into l-kynurenine (Kyn), a metabolite endowed with anti-inflammatory and immunoregulatory effects. In dendritic cells, IL-6 induces IDO1 proteasomal degradation and shuts down IDO1-mediated immunosuppressive effects. In tumor cells, IL-6 upregulates IDO1 expression and favors tumor immune escape mechanisms. To investigate the role of IDO1 and its possible relationship with IL-6 in obesity, we induced the disease by feeding mice with a high fat diet (HFD). Mice on a standard diet were used as control. Experimental obesity was associated with high IDO1 expression and Kyn levels in the stromal vascular fraction of visceral white adipose tissue (SVF WAT). IDO1-deficient mice on HFD gained less weight and were less insulin resistant as compared to wild type counterparts. Administration of tocilizumab (TCZ), an IL-6 receptor (IL-6R) antagonist, to mice on HFD significantly reduced weight gain, controlled adipose tissue hypertrophy, increased insulin sensitivity, and induced a better glucose tolerance. TCZ also induced a dramatic inhibition of IDO1 expression and Kyn production in the SVF WAT. Thus our data indicated that the IL-6/IDO1 axis may play a pathogenetic role in a chronic, low-grade inflammation condition, and, perhaps most importantly, IL-6R blockade may be considered a valid option for obesity treatment.

Keywords: IL-6 receptor (IL-6R); experimental obesity; high fat diet (HFD); indoleamine 2, 3 dioxygenase 1 (IDO1); tocilizumab (TCZ); tryptophan metabolism; white adipose tissue (WAT)

DOI: https://doi.org/10.3389/fimmu.2021.713989

Nat Commun. 2021 Aug 20. 12(1): 5068

O-GlcNAcylated p53 in the liver modulates hepatic glucose production.

p53 regulates several signaling pathways to maintain the metabolic homeostasis of cells and modulates the cellular response to stress. Deficiency or excess of nutrients causes cellular metabolic stress, and we hypothesized that p53 could be linked to glucose maintenance. We show here that upon starvation hepatic p53 is stabilized by O-GlcNAcylation and plays an essential role in the physiological regulation of glucose homeostasis. More specifically, p53 binds to PCK1 promoter and regulates its transcriptional activation, thereby controlling hepatic glucose production. Mice lacking p53 in the liver show a reduced gluconeogenic response during calorie restriction. Glucagon, adrenaline and glucocorticoids augment protein levels of p53, and administration of these hormones to p53 deficient human hepatocytes and to liver-specific p53 deficient mice fails to increase glucose levels. Moreover, insulin decreases p53 levels, and over-expression of p53 impairs insulin sensitivity. Finally, protein levels of p53, as well as genes responsible of O-GlcNAcylation are elevated in the liver of type 2 diabetic patients and positively correlate with glucose and HOMA-IR. Overall these results indicate that the O-GlcNAcylation of p53 plays an unsuspected key role regulating in vivo glucose homeostasis.

DOI: https://doi.org/10.1038/s41467-021-25390-0