bims-stacyt 2020-07-05 papers

IUBMB Life. 2020 Jun 27.

Anterior gradient 2 promotes tumorigenesis through upregulation of CCAAT-enhancer binding protein beta and hypoxia-inducible factor-2α and subsequent secretion of interleukin-6, interleukin-8, and vascular endothelial growth factor in the Caki-1 clear cell renal cell carcinoma cell line.

Kinga Pajdzik, Mateusz Wilamowski, Dariusz Żurawek, Kinga B Stopa, Michał Nodzyński, Agata Kalita, Jolanta Jura.

It has been previously established that hypoxia leads to tumor development, treatment resistance, and a poor prognosis. Under oxygen deprivation, hypoxia-inducible factors (HIFs) are stimulated to activate the genes necessary for tumor development in a low-oxygen environment. These genes encode regulators of angiogenesis, epithelial-mesenchymal transition, and cellular metabolism. A disulfide isomerase, anterior gradient 2 (AGR2), has been shown to increase hypoxia-inducible factor 1, alpha subunit (HIF-1α) stability in breast cancer. Our goal was to determine if AGR2 affects the level of transcription factor hypoxia-inducible factor 2, alpha subunit (HIF-2α). As a model, we used the clear cell renal cell carcinoma (ccRCC) cell line Caki-1. The cells were transduced with lentiviral vector (Tet-On) encoding AGR2. After induction of AGR2 expression, cells were grown under either hypoxic (0.5% O2 ) or normoxic (21% O2 ) conditions. Our data showed that AGR2 upregulated both HIF-1α and HIF-2α expression in Caki-1 cells increasing the expression of HIF-activated genes (glucose transporter 1, phosphoglycerate kinase 1, vascular endothelial growth factor A, and transforming growth factor-alpha) under the hypoxic conditions. Under the normoxic conditions, AGR2 strongly activated CCAAT-enhancer binding protein beta (C/EBPβ). Upregulation of C/EBPβ correlated with increased expression and secretion of the interleukin-6 and interleukin-8, inducing angiogenesis and inflammation in Caki-1 cells. In summary, our studies revealed that AGR2 has essential functions in ccRCC progression through upregulation of C/EBPβ and HIF-2α expressions, which affects cell signaling and metabolism.

Keywords: C/EBP-beta; anterior gradient 2 protein; carcinogenesis; hypoxia; hypoxia-inducible factors; inflammation

DOI: https://doi.org/10.1002/iub.2331

Trends Cancer. 2020 Jul;pii: S2405-8033(20)30084-4. [Epub ahead of print]6(7): 593-604

Drilling for Oil: Tumor-Surrounding Adipocytes Fueling Cancer.

Camille Attané, Catherine Muller.

Over the past decade, it has become apparent that metabolic reprogramming is a key event in tumor progression. The tumor microenvironment (TME) is a source of metabolites for tumor cells. Lipid-filled mature adipocytes are frequently found in proximity to invasive human tumors and release free fatty acids (FFAs) through lipolysis. These FFAs are taken up by tumor cells and used to promote tumor progression by mechanisms that include mitochondrial fatty acid oxidation (FAO). This review discusses recent advances in our understanding of this metabolic symbiosis between adipocytes and cancer cells and underlines the differences in this metabolic crosstalk between the various types of cancer and their localization.

Keywords: adipocyte; cancer metabolism; fatty acids; metabolic crosstalk

DOI: https://doi.org/10.1016/j.trecan.2020.03.001

Arthritis Rheumatol. 2020 Jun 30.

Proinflammatory profile of autoimmune CD8+ T cells relies on increased LDHA activity and aerobic glycolysis.

M Margarida Souto-Carneiro, Karel D Klika, Mónica T Abreu, André P Meyer, Rainer Saffrich, Roger Sandhoff, Richard Jennemann, Franziska V Kraus, Lars Tykocinski, Volker Eckstein, Lina Carvalho, Mark Kriegsmann, Thomas Giese, Hanns-Martin Lorenz, Rui A Carvalho.

OBJECTIVES: CD8+ T cells (CD8) contribute to rheumatoid arthritis (RA) by releasing pro-inflammatory and cytolytic mediators, even in a challenging hypoxic and nutrient-poor microenvironment like the synovial membrane (SM). Here we explore the mechanisms through which RA CD8 meet their metabolic demands.
METHODS: Purified blood CD8 from RA, PsA, SpA and control individuals, and from RA SM were stimulated in media containing 13 C-labeled metabolic substrates in the presence or absence of metabolic inhibitors under normoxia or hypoxia. The production of metabolic intermediates was quantified by 1 H nuclear magnetic resonance. The expression of metabolic enzymes, transcription factors and immune effector molecules was assessed at mRNA and protein levels. Functional studies were performed.
RESULTS: Blood RA CD8 met their metabolic demands through aerobic glycolysis (uniformly 13 C-enriched lactate in RA: 2.6 to 3.7-fold higher than SpA, PsA and controls, p<0.01) and glutaminolysis. Overexpression of Warburg effect-linked enzymes in all RA CD8 subsets maintained this metabolic profile, conferring RA CD8 the capacity to proliferate under hypoxia and low glucose conditions. LDHA was overexpressed at mRNA (n=6/group, p<0.03) and protein (RA n=17, controls n=9, p<0.05) levels in all RA subsets. Inhibition of LDHA with FX11 reduced lipogenesis, migration, proliferation and effector functions in RA CD8, while increasing ROS production 1.5-fold (p<0.03). Under FX11, RA CD8 lost their capacity to induce healthy B cells to develop a pro-inflammatory phenotype. Similar metabolic alterations were observed in SM RA CD8.
CONCLUSION: Remodeling glucose and glutamine metabolism in RA CD8 by targeting LDHA activity can reduce their deleterious inflammatory and cytolytic contribution to autoimmunity.

DOI: https://doi.org/10.1002/art.41420

Cell. 2020 Jun 27. pii: S0092-8674(20)30687-5. [Epub ahead of print]

Origin and Function of Stress-Induced IL-6 in Murine Models.

Hua Qing, Reina Desrouleaux, Kavita Israni-Winger, Yann S Mineur, Nia Fogelman, Cuiling Zhang, Saleh Rashed, Noah W Palm, Rajita Sinha, Marina R Picciotto, Rachel J Perry, Andrew Wang.

Acute psychological stress has long been known to decrease host fitness to inflammation in a wide variety of diseases, but how this occurs is incompletely understood. Using mouse models, we show that interleukin-6 (IL-6) is the dominant cytokine inducible upon acute stress alone. Stress-inducible IL-6 is produced from brown adipocytes in a beta-3-adrenergic-receptor-dependent fashion. During stress, endocrine IL-6 is the required instructive signal for mediating hyperglycemia through hepatic gluconeogenesis, which is necessary for anticipating and fueling "fight or flight" responses. This adaptation comes at the cost of enhancing mortality to a subsequent inflammatory challenge. These findings provide a mechanistic understanding of the ontogeny and adaptive purpose of IL-6 as a bona fide stress hormone coordinating systemic immunometabolic reprogramming. This brain-brown fat-liver axis might provide new insights into brown adipose tissue as a stress-responsive endocrine organ and mechanistic insight into targeting this axis in the treatment of inflammatory and neuropsychiatric diseases.

Keywords: IL-6; acute stress; beta-adrenergic receptors; brown adipose tissue; gluconeogenesis; immunometabolism; inflammation; neuroendocrine-immune axis; neuroimmunology; tolerance

DOI: https://doi.org/10.1016/j.cell.2020.05.054